Gene Report

Basic Information

Approved Symbol	MAPK1
Approved Name	mitogen-activated protein kinase 1
Previous Symbol	PRKM2, PRKM1
Symbol Alias	ERK, ERK2, p41mapk, MAPK2
Location	22q11.2
Position	chr22:22113946-22221970 (-)
External Links	Entrez Gene: 5594 Ensembl: ENSG00000100030 UCSC: uc002zvn.3 HGNC ID: 6871
No. of Studies (Positive/Negative)	2(2/0)
Type	Literature-origin

Positive relationships between MAPK1 and MDD (count: 2)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
mitogen-activated protein kinase (MAPK) phosphatase-1	Duric, 2010	patients and normal controls		Whole-genome expression profiling of postmortem tissue shows...... Whole-genome expression profiling of postmortem tissue shows significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1, but hereafter called MKP-1) in the hippocampal subfields of subjects with MDD compared to matched controls. More...
MAPK1	Sibille E, 2009	animal model; patients and nomal controls	R=0.88, P-value<5E-6; y slope=1.14	Downregulated in MDD patients Downregulated in MDD patients

Positive relationships between MAPK1 and other components at different levels (count: 0)

Positive relationship network of MAPK1 in MK4MDD

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Note:
1. The different color of the nodes denotes the level of the nodes.

Genetic/Epigenetic Locus	Protein and Other Molecule	Cell and Molecular Pathway	Neural System	Cognition and Behavior	Symptoms and Signs	Environment	MDD

2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network. If the mapped gene or protein is not from literature, square node would be used instead of Circle node. Accordingly, the relationship is marked with dot line.
2. User can drag the nodes to rearrange the layout of the network. Click the node will enter the report page of the node. Right-click will show also the menus to link to the report page of the node and remove the node and related edges. Hover the node will show the level of the node and hover the edge will show the evidence/description of the edge.
3. The network is generated using Cytoscape Web

Negative relationships between MAPK1 and MDD (count: 0)

Negative relationships between MAPK1 and other components at different levels (count: 0)

MAPK1 related SNPs in MK4MDD (count: 0)

MAPK1 related proteins in MK4MDD (count: 1)

Approved Name	UniportKB	No. of Studies (Positive/Negative)	Source
Mitogen-activated protein kinase 1	P28482	0(0/0)	Gene mapped

MAPK1 related GO terms (count: 95)

ID	Name	Type	Evidence
Literature-origin GO terms
GO:0006950	response to stress	biological process	TAS[10958679]
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0007268	synaptic transmission	biological process	TAS
GO:0006915	apoptotic process	biological process	IEA
GO:0005856	cytoskeleton	cellular component	TAS[19565474]
GO:0000165	MAPK cascade	biological process	TAS

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0015630	microtubule cytoskeleton	cellular component	IDA
GO:0045727	positive regulation of translation	biological process	IEA
GO:0051493	regulation of cytoskeleton organization	biological process	TAS[19565474]
GO:0002755	MyD88-dependent toll-like receptor signaling pathway	biological process	TAS
GO:0004674	protein serine/threonine kinase activity	molecular function	IDA[15850461]
GO:0008353	RNA polymerase II carboxy-terminal domain kinase activity	molecular function	ISS
GO:0034138	toll-like receptor 3 signaling pathway	biological process	TAS
GO:0018105	peptidyl-serine phosphorylation	biological process	IDA[15850461]
GO:0043234	protein complex	cellular component	IEA
GO:0007049	cell cycle	biological process	IEA
GO:0005737	cytoplasm	cellular component	IDA[18794356]
GO:0032872	regulation of stress-activated MAPK cascade	biological process	TAS[19565474]
GO:0043627	response to estrogen stimulus	biological process	IEA
GO:0005654	nucleoplasm	cellular component	TAS
GO:0007165	signal transduction	biological process	TAS[1540184]
GO:0050852	T cell receptor signaling pathway	biological process	IEA
GO:0034130	toll-like receptor 1 signaling pathway	biological process	TAS
GO:0001784	phosphotyrosine binding	molecular function	IEA
GO:0005901	caveola	cellular component	TAS[19565474]
GO:0051090	regulation of sequence-specific DNA binding transcription factor activity	biological process	TAS
GO:0031435	mitogen-activated protein kinase kinase kinase binding	molecular function	IEA
GO:0045596	negative regulation of cell differentiation	biological process	IEA
GO:0006974	response to DNA damage stimulus	biological process	IEA
GO:0072584	caveolin-mediated endocytosis	biological process	TAS[19565474]
GO:0030168	platelet activation	biological process	TAS
GO:0005730	nucleolus	cellular component	IDA
GO:0002756	MyD88-independent toll-like receptor signaling pathway	biological process	TAS
GO:0007596	blood coagulation	biological process	TAS
GO:0043330	response to exogenous dsRNA	biological process	IEA
GO:0045087	innate immune response	biological process	TAS
GO:0034142	toll-like receptor 4 signaling pathway	biological process	TAS
GO:0006917	induction of apoptosis	biological process	TAS[10958679]
GO:0005925	focal adhesion	cellular component	TAS[19565474]
GO:0006351	transcription, DNA-dependent	biological process	IEA
GO:0008063	Toll signaling pathway	biological process	TAS
GO:0005739	mitochondrion	cellular component	TAS[19565474]
GO:0090170	regulation of Golgi inheritance	biological process	TAS[19565474]
GO:0060716	labyrinthine layer blood vessel development	biological process	IEA
GO:0005770	late endosome	cellular component	TAS[19565474]
GO:0005769	early endosome	cellular component	TAS[19565474]
GO:2000641	regulation of early endosome to late endosome transport	biological process	TAS[19565474]
GO:0060397	JAK-STAT cascade involved in growth hormone signaling pathway	biological process	TAS
GO:0030335	positive regulation of cell migration	biological process	IEA
GO:0000186	activation of MAPKK activity	biological process	TAS
GO:0019048	virus-host interaction	biological process	IEA
GO:0033598	mammary gland epithelial cell proliferation	biological process	IEA
GO:0000187	activation of MAPK activity	biological process	TAS
GO:0005524	ATP binding	molecular function	IEA
GO:0005819	spindle	cellular component	IEA
GO:0007264	small GTPase mediated signal transduction	biological process	TAS
GO:0019902	phosphatase binding	molecular function	IPI[19494114]
GO:0002224	toll-like receptor signaling pathway	biological process	TAS
GO:0006935	chemotaxis	biological process	TAS[10706854]
GO:0005794	Golgi apparatus	cellular component	TAS[19565474]
GO:0070371	ERK1 and ERK2 cascade	biological process	IDA[16314496]; TAS
GO:0000189	MAPK import into nucleus	biological process	IEA
GO:0004707	MAP kinase activity	molecular function	IEA
GO:0045893	positive regulation of transcription, DNA-dependent	biological process	IEA
GO:0003677	DNA binding	molecular function	IEA
GO:0007173	epidermal growth factor receptor signaling pathway	biological process	TAS
GO:0032839	dendrite cytoplasm	cellular component	IEA
GO:0008134	transcription factor binding	molecular function	IEA
GO:0008286	insulin receptor signaling pathway	biological process	TAS
GO:0031663	lipopolysaccharide-mediated signaling pathway	biological process	IEA
GO:0048011	nerve growth factor receptor signaling pathway	biological process	TAS
GO:0033267	axon part	cellular component	IEA
GO:0034134	toll-like receptor 2 signaling pathway	biological process	TAS
GO:0010800	positive regulation of peptidyl-threonine phosphorylation	biological process	IDA[16314496]
GO:0005515	protein binding	molecular function	IPI[16286470]
GO:0043204	perikaryon	cellular component	IEA
GO:0005634	nucleus	cellular component	IDA; TAS[19565474]
GO:0009636	response to toxin	biological process	IEA
GO:0009887	organ morphogenesis	biological process	IEA
GO:0050853	B cell receptor signaling pathway	biological process	IEA
GO:0008543	fibroblast growth factor receptor signaling pathway	biological process	TAS
GO:0051403	stress-activated MAPK cascade	biological process	TAS
GO:0007411	axon guidance	biological process	TAS
GO:0007265	Ras protein signal transduction	biological process	TAS
GO:0070849	response to epidermal growth factor stimulus	biological process	IDA[18794356]
GO:0005829	cytosol	cellular component	TAS
GO:0005815	microtubule organizing center	cellular component	IEA
GO:0019858	cytosine metabolic process	biological process	IEA
GO:0035666	TRIF-dependent toll-like receptor signaling pathway	biological process	TAS
GO:0019233	sensory perception of pain	biological process	IEA
GO:0031143	pseudopodium	cellular component	IEA
GO:0008284	positive regulation of cell proliferation	biological process	IEA

MAPK1 related KEGG pathways (count: 46)

ID	Name	Brief Description	Full Description
Literature-origin KEGG pathway
hsa04510	focal adhesion	Focal adhesion	Cell-matrix adhesions play essential roles in important biol...... Cell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the cell-extracellular matrix contact points, specialized structures are formed and termed focal adhesions, where bundles of actin filaments are anchored to transmembrane receptors of the integrin family through a multi-molecular complex of junctional plaque proteins. Some of the constituents of focal adhesions participate in the structural link between membrane receptors and the actin cytoskeleton, while others are signalling molecules, including different protein kinases and phosphatases, their substrates, and various adapter proteins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK, src and Shc to initiate downstream signaling events. These signalling events culminate in reorganization of the actin cytoskeleton; a prerequisite for changes in cell shape and motility, and gene expression. Similar morphological alterations and modulation of gene expression are initiated by the binding of growth factors to their respective receptors, emphasizing the considerable crosstalk between adhesion- and growth factor-mediated signalling. More...
hsa04360	axon guidance	Axon guidance	Axon guidance represents a key stage in the formation of neu...... Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as netrins, ephrins, Slits, and semaphorins. These guidance cues are read by growth cone receptors, and signal transduction pathways downstream of these receptors converge onto the Rho GTPases to elicit changes in cytoskeletal organization that determine which way the growth cone will turn. More...
hsa04730	long term_depression	Long-term depression	Cerebellar long-term depression (LTD), thought to be a molec...... Cerebellar long-term depression (LTD), thought to be a molecular and cellular basis for cerebellar learning, is a process involving a decrease in the synaptic strength between parallel fiber (PF) and Purkinje cells (PCs) induced by the conjunctive activation of PFs and climbing fiber (CF). Multiple signal transduction pathways have been shown to be involved in this process. Activation of PFs terminating on spines in dendritic branchlets leads to glutamate release and activation of both AMPA and mGluRs. Activation of CFs, which make multiple synaptic contacts on proximal dendrites, also via AMPA receptors, opens voltage-gated calcium channels (VGCCs) and causes a generalized influx of calcium. These cellular signals, generated from two different synaptic origins, trigger a cascade of events culminating in a phosphorylation-dependent, long-term reduction in AMPA receptor sensitivity at the PF-PC synapse. This may take place either through receptor internalization and/or through receptor desensitization. More...
hsa04810	regulation of_actin_cytoskeleton	Regulation of actin cytoskeleton
hsa04150	mtor signaling_pathway	mTOR signaling pathway
hsa04270	vascular smooth_muscle_contraction	Vascular smooth muscle contraction	The vascular smooth muscle cell (VSMC) is a highly specializ...... The vascular smooth muscle cell (VSMC) is a highly specialized cell whose principal function is contraction. On contraction, VSMCs shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure. The principal mechanisms that regulate the contractile state of VSMCs are changes in cytosolic Ca2+ concentration (c). In response to vasoconstrictor stimuli, Ca2+ is mobilized from intracellular stores and/or the extracellular space to increase c in VSMCs. The increase in c, in turn, activates the Ca2+-CaM-MLCK pathway and stimulates MLC20 phosphorylation, leading to myosin-actin interactions and, hence, the development of contractile force. The sensitivity of contractile myofilaments or MLC20 phosphorylation to Ca2+ can be secondarily modulated by other signaling pathways. During receptor stimulation, the contractile force is greatly enhanced by the inhibition of myosin phosphatase. Rho/Rho kinase, PKC, and arachidonic acid have been proposed to play a pivotal role in this enhancement. The signaling events that mediate relaxation include the removal of a contractile agonist (passive relaxation) and activation of cyclic nucleotide-dependent signaling pathways in the continued presence of a contractile agonist (active relaxation). Active relaxation occurs through the inhibition of both Ca2+ mobilization and myofilament Ca2+ sensitivity in VSMCs. More...

ID	Name	Brief Description	Full Description
Gene mapped KEGG pathways
hsa05221	acute myeloid_leukemia	Acute myeloid leukemia	Two major types of genetic events are crucial for the molecu...... Two major types of genetic events are crucial for the molecular pathogenesis of acute myeloid leukemias (AML) : activating mutations of signal transduction intermediates and alterations in myeloid transcription factors governing hematopoietic differentiation. Both aberrant and constitutive activation of signal transduction molecules are found in about 50% of primary AML bone marrow samples, and seem to contribute to the increased proliferation and apoptosis resistance. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Specific haematopoietic transcription factors are crucial for differentiation to particular lineages during normal differentiation, but are frequently disrupted in AML. Some mechanisms of disruption involve the effect of fusion proteins that are generated by chromosomal translocations on haematopoietic transcription factors. In other cases, the transcription factors themselves are mutated. More...
hsa04720	long term_potentiation	Long-term potentiation	Hippocampal long-term potentiation (LTP), a long-lasting inc...... Hippocampal long-term potentiation (LTP), a long-lasting increase in synaptic efficacy, is the molecular basis for learning and memory. Tetanic stimulation of afferents in the CA1 region of the hippocampus induces glutamate release and activation of glutamate receptors in dendritic spines. A large increase in i resulting from influx through NMDA receptors leads to constitutive activation of CaM kinase II (CaM KII). Constitutively active CaM kinase II phosphorylates AMPA receptors, resulting in potentiation of the ionic conductance of AMPA receptors. Early-phase LTP (E-LTP) expression is due, in part, to this phosphorylation of the AMPA receptor. It is hypothesized that postsynaptic Ca2+ increases generated through NMDA receptors activate several signal transduction pathways including the Erk/MAP kinase and cAMP regulatory pathways. The convergence of these pathways at the level of the CREB/CRE transcriptional pathway may increase expression of a family of genes required for late-phase LTP (L-LTP). More...
hsa04916	melanogenesis	Melanogenesis	Cutaneous melanin pigment plays a critical role in camouflag...... Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortic peptides. MC1R activates the cyclic AMP (cAMP) response-element binding protein (CREB). Increased expression of MITF and its activation by phosphorylation (P) stimulate the transcription of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT), which produce melanin. Melanin synthesis takes place within specialized intracellular organelles named melanosomes. Melanin-containing melanosomes then move from the perinuclear region to the dendrite tips and are transferred to keratinocytes by a still not well-characterized mechanism. More...
hsa05200	pathways in_cancer	Pathways in cancer
hsa05210	colorectal cancer	Colorectal cancer	Classically, colorectal cancer (CRC) has been believed to de...... Classically, colorectal cancer (CRC) has been believed to develop from normal mucosa through the premalignant adenoma by the step-wise accumulation of mutations. All CRC display either microsatellite instability (MSI) or chromosome instability (CIN). MSI occurs in 15% of colon cancers and results from inactivation of the DNA mismatch repair (MMR) system by either MMR gene mutations or hypermethylation of the MLH1 promoter. MSI promotes tumorigenesis through generating mutations in target genes that possess coding microsatellite repeats, such as beta-catenin, TGFBR2 and BAX. CIN is found in the majority of colon cancers and leads to a different pattern of gene alterations that contribute to tumor formation. Genes involved in CIN are those coding for APC, K-ras, SMAD4 and p53. More...
hsa04520	adherens junction	Adherens junction	Cell-cell adherens junctions (AJs), the most common type of ...... Cell-cell adherens junctions (AJs), the most common type of intercellular adhesions, are important for maintaining tissue architecture and cell polarity and can limit cell movement and proliferation. At AJs, E-cadherin serves as an essential cell adhesion molecules (CAMs). The cytoplasmic tail binds beta-catenin, which in turn binds alpha-catenin. Alpha-catenin is associated with F-actin bundles directly and indirectly. The integrity of the cadherin-catenin complex is negatively regulated by phosphorylation of beta-catenin by receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases (Fer, Fyn, Yes, and Src), which leads to dissociation of the cadherin-catenin complex. Integrity of this complex is positively regulated by beta -catenin phosphorylation by casein kinase II, and dephosphorylation by protein tyrosine phosphatases. Changes in the phosphorylation state of beta-catenin affect cell-cell adhesion, cell migration and the level of signaling beta-catenin. Wnt signaling acts as a positive regulator of beta-catenin by inhibiting beta-catenin degradation, which stabilizes beta-catenin, and causes its accumulation. Cadherin may acts as a negative regulator of signaling beta-catenin as it binds beta-catenin at the cell surface and thereby sequesters it from the nucleus. Nectins also function as CAMs at AJs, but are more highly concentrated at AJs than E-cadherin. Nectins transduce signals through Cdc42 and Rac, which reorganize the actin cytoskeleton, regulate the formation of AJs, and strengthen cell-cell adhesion. More...
hsa04621	nod like_receptor_signaling_pathway	NOD-like receptor signaling pathway	Specific families of pattern recognition receptors are respo...... Specific families of pattern recognition receptors are responsible for detecting various pathogens and generating innate immune responses. The intracellular NOD-like receptor (NLR) family contains more than 20 members in mammals and plays a pivotal role in the recognition of intracellular ligands. NOD1 and NOD2, two prototypic NLRs, sense the cytosolic presence of the bacterial peptidoglycan fragments that escaped from endosomal compartments, driving the activation of NF-{kappa}B and MAPK, cytokine production and apoptosis. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of multiprotein complexes called inflammasomes. These NLRs include NALP1, NALP3 and Ipaf. The inflammasomes are critical for generating mature proinflammatory cytokines in concert with Toll-like receptor signaling pathway. More...
hsa04062	chemokine signaling_pathway	Chemokine signaling pathway	Inflammatory immune response requires the recruitment of leu...... Inflammatory immune response requires the recruitment of leukocytes to the site of inflammation upon foreign insult. Chemokines are small chemoattractant peptides that provide directional cues for the cell trafficking and thus are vital for protective host response. In addition, chemokines regulate plethora of biological processes of hematopoietic cells to lead cellular activation, differentiation and survival. The chemokine signal is transduced by chemokine receptors (G-protein coupled receptors) expressed on the immune cells. After receptor activation, the alpha- and beta-gamma-subunits of G protein dissociate to activate diverse downstream pathways resulting in cellular polarization and actin reorganization. Various members of small GTPases are involved in this process. Induction of nitric oxide and production of reactive oxygen species are as well regulated by chemokine signal via calcium mobilization and diacylglycerol production. More...
hsa05214	glioma	Glioma	Glioblastoma multiforme (GBM) formation is either de novo (p...... Glioblastoma multiforme (GBM) formation is either de novo (primary GBMs) or due to the progression of a lower grade glioma to a higher grade one through the acquisition of additional mutations (secondary GBMs). In primary GBM, disruption of the p53 pathway often occurs through loss of ARF, or less frequently through amplification of MDM2. Disruption of the RB pathway occurs through loss of INK4A. Amplification and/or mutation of the epidermal growth factor receptor (EGFR) is the most frequently detected genetic defect that is associated with primary GBM. In secondary GBM, loss of p53 and activation of the growth-factorreceptor-tyrosine-kinase signalling pathway (such as through overexpression of PDGF/PDGFR ) initiates tumour formation,whereas disruption of the retinoblastoma (RB) pathway contributes to the progression of tumour development. Loss of PTEN has been implicated in both pathways, although it is much more common in the pathogenesis of primary GBM. More...
hsa05223	non small_cell_lung_cancer	Non-small cell lung cancer	Non-small-cell lung cancer (NSCLC) accounts for approximatel...... Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS and c-erbB-2, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Overexpression of c-erbB-2 or EGFR leads to a proliferative advantage. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector.Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect. More...
hsa05218	melanoma	Melanoma	Five distinct stages have been proposed in the evolution of ...... Five distinct stages have been proposed in the evolution of melanoma on the basis of histological criteria: common acquired and congenital nevi without dysplastic changes; dysplastic nevi with structural and architectural atypia; radial-growth phase (RGP) melanoma; vertical-growth phase (VGP) melanoma; and metastatic melanoma. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Moreover, melanoma development is strongly associated with inactivation of the p16INK4a/CDK4,6/pRb and p14ARF/HMD2/p53 tumor suppressor pathways. The vertical-growth phase and metastatic melanoma are notable for striking changes in the control of cell adhesion. Recently, amplification of the MITF gene was demonstrated in 10% of primary melanomas and 20% of metastatic melanomas, suggesting that MITF is a melanoma oncogene. More...
hsa05219	bladder cancer	Bladder cancer	Bladder cancer arise and progress along two distinctive path...... Bladder cancer arise and progress along two distinctive pathways. The first of these is often preceded by simple and papillary hyperplasia and exhibits a tumour morphology that is low-grade, superficial and papillary. Papillary carcinoma has a tendency to recur locally, but rarely invades and metastasizes. These tumors frequently show a constitutive activation of the receptor tyrosine kinase-Ras pathway, exhibiting activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes. The second tumour pathway is characterized by high-grade muscle-invasive tumours, which either originate from flat carcinoma in situ (CIS)/severe dysplasia or arise de novo. Over half of these tumours show defects in the tumour suppressors p53 and/or the retinoblastoma protein (RB) genes and pathways, and over 50% of these tumours progress to local and distant metastases. Some of the cell cycle-related molecules show evidence of epigenetic modulation through aberrant promoter hypermethylation in invasive bladder cancer. Invasion and metastases are promoted by several factors that alter the tumour microenvironment, including the aberrant expression of E-cadherins (E-cad), matrix metalloproteinases (MMPs), angiogenic factors such as vascular endothelial growth factor (VEGF). More...
hsa04910	insulin signaling_pathway	Insulin signaling pathway	Insulin binding to its receptor results in the tyrosine phos...... Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR. Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1. More...
hsa04930	type ii_diabetes_mellitus	Type II diabetes mellitus	Insulin resistance is strongly associated with type II diabe...... Insulin resistance is strongly associated with type II diabetes. Diabetogenic factors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process. The development of type II diabetes requires impaired beta-cell function. Chronic hyperglycemia has been shown to induce multiple defects in beta-cells. Hyperglycemia has been proposed to lead to large amounts of reactive oxygen species (ROS) in beta-cells, with subsequent damage to cellular components including PDX-1. Loss of PDX-1, a critical regulator of insulin promoter activity, has also been proposed as an important mechanism leading to beta-cell dysfunction. Although there is little doubt as to the importance of genetic factors in type II diabetes, genetic analysis is difficult due to complex interaction among multiple susceptibility genes and between genetic and environmental factors. Genetic studies have therefore given very diverse results. Kir6.2 and IRS are two of the candidate genes. It is known that Kir6.2 and IRS play central roles in insulin secretion and insulin signal transmission, respectively. More...
hsa05140	leishmania infection	Leishmania infection	Leishmania is an intracellular protozoan parasite of macroph...... Leishmania is an intracellular protozoan parasite of macrophages that causes visceral, mucosal, and cutaneous diseases. The parasite is transmitted to humans by sandflies, where they survive and proliferate intracellularly by deactivating the macrophage. Successful infection of Leishmania is achieved by alteration of signaling events in the host cell, leading to enhanced production of the autoinhibitory molecules like TGF-beta and decreased induction of cytokines such as IL12 for protective immunity. Nitric oxide production is also inhibited. In addition, defective expression of major histocompatibility complex (MHC) genes silences subsequent T cell activation mediated by macrophages, resulting in abnormal immune responses. More...
hsa05220	chronic myeloid_leukemia	Chronic myeloid leukemia	Chronic myelogenous leukaemia (CML) is a biphasic disease, i...... Chronic myelogenous leukaemia (CML) is a biphasic disease, initiated by expression of the BCR/ABL fusion gene product in self-renewing, haematopoietic stem cells (HSCs). HSCs can differentiate into common myeloid progenitors (CMPs), which then differentiate into granulocyte/macrophage progenitors (GMPs). HSCs can also differentiate into common lymphoid progenitors (CLPs), which are the progenitors of lymphocytes such as T cells and B cells. The initial chronic phase of CML (CML-CP) is characterized by a massive expansion of the granulocytic-cell series. Acquisition of additional genetic mutations beyond expression of BCR/ABL causes the progression of CML from chronic phase to blast phase (CML-BP), characterized by an accumulation of myeloid or lymphoid blast cells. The BCR/ABL fusion gene encodes p210BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. The tyrosine kinase activity is essential for cell transformation and the cytoplasmic localization of BCR/ABL allows the assembly of phosphorylated substrates in multiprotein complexes that transmit mitogenic and antiapoptotic signals. Additional cytogenetic and molecular changes are frequently found in patients with CML during the progression of the disease from chronic to blast phase. Some of the genetic changes include mutations in TP53, RB, and CDKN2A (also known as p16INK4A), or overexpression of genes such as EVI1. Additional chromosome translocations are also observed, such as t(3;21)(q26;q22), which generates AML1/EVI1. AML1/EVI-1 represses TGF-beta-mediated growth inhibitory signal. More...
hsa04620	toll like_receptor_signaling_pathway	Toll-like receptor signaling pathway	Specific families of pattern recognition receptors are respo...... Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK. More...
hsa04114	oocyte meiosis	Oocyte meiosis	During meiosis, a single round of DNA replication is followe...... During meiosis, a single round of DNA replication is followed by two rounds of chromosome segregation, called meiosis I and meiosis II. At meiosis I, homologous chromosomes recombine and then segregate to opposite poles, while the sister chromatids segregate from each other at meoisis II. In vertebrates, immature oocytes are arrested at the PI (prophase of meiosis I). The resumption of meiosis is stimulated by progesterone, which carries the oocyte through two consecutive M-phases (MI and MII) to a second arrest at MII. The key activity driving meiotic progression is the MPF (maturation-promoting factor), a heterodimer of CDC2 (cell division cycle 2 kinase) and cyclin B. In PI-arrested oocytes, MPF is initially inactive and is activated by the dual-specificity CDC25C phosphatase as the result of new synthesis of Mos induced by progesterone. MPF activation mediates the transition from the PI arrest to MI. The subsequent decrease in MPF levels, required to exit from MI into interkinesis, is induced by a negative feedback loop, where CDC2 brings about the activation of the APC (anaphase-promoting complex), which mediates destruction of cyclin B. Re-activation of MPF for MII requires re-accumulation of high levels of cyclin B as well as the inactivation of the APC by newly synthesized Emi2 and other components of the CSF (cytostatic factor), such as cyclin E or high levels of Mos. CSF antagonizes the ubiquitin ligase activity of the APC, preventing cyclin B destruction and meiotic exit until fertilization occurs. Fertilization triggers a transient increase in cytosolic free Ca2+, which leads to CSF inactivation and cyclin B destruction through the APC. Then eggs are released from MII into the first embryonic cell cycle. More...
hsa05211	renal cell_carcinoma	Renal cell carcinoma	Renal cell carcinoma (RCC) is a heterogenous term comprising...... Renal cell carcinoma (RCC) is a heterogenous term comprising a group of neoplasms of renal origin. There are 4 major histologic subtypes of RCC: conventional (clear cell RCC, 75%), papillary (15%), chromophobic (5%), and collecting duct (2%). Multiple genes are involved in the molecular pathogenesis of RCC. VHL is a tumor suppressor gene responsible for hereditary (von Hippel-Lindau) and sporadic variants of conventional (clear cell) RCC. In the absence of VHL, hypoxia-inducible factor alpha (HIF-alpha) accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. An oncogene, MET has been found to be mutant in cases of hereditary papillary renal cancer (HPRC), although the incidence of c-MET mutations is low in sporadic papillary RCC. Once activated, MET mediates a number of biological effects including motility, invasion of extracellular matrix, cellular transformation, prevention of apoptosis and metastasis formation. Mutations in the fumarate hydratase (FH) gene cause hereditary leiomyomatosis and renal cancer syndrome (HLRCC) papillary renal tumors, although the incidence of FH mutations in sporadic tumors is unknown. Loss of functional FH leads to accumulation of fumarate in the cell, triggering inhibition of HPH and preventing targeted pVHL-mediated degradation of HIF-alpha. BHD mutations cause the Birt-Hogg-Dube syndrome and its associated chromophobe, hybrid oncocytic, and conventional (clear cell) RCC. The incidence of BHD mutations in sporadic renal tumors is not known. More...
hsa05215	prostate cancer	Prostate cancer	The identification of key molecular alterations in prostate-...... The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes that catalyze conjunction of glutathione with harmful, electrophilic molecules, thereby protecting cells from carcinogenic factors. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by such carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. After therapeutic reduction in the levels of testosterone and dihydrotestosterone, the emergence of androgen-independent prostate cancer has been associated with mutations in the androgen receptor (AR) that permit receptor activation by other ligands, increased expression of androgen receptors accompanying AR amplification, and ligand-independent androgen-receptor activation. More...
hsa04664	fc epsilon_ri_signaling_pathway	Fc epsilon RI signaling pathway	Fc epsilon RI-mediated signaling pathways in mast cells are ...... Fc epsilon RI-mediated signaling pathways in mast cells are initiated by the interaction of antigen (Ag) with IgE bound to the extracellular domain of the alpha chain of Fc epsilon RI. The activation pathways are regulated both positively and negatively by the interactions of numerous signaling molecules. Mast cells that are thus activated release preformed granules which contain biogenic amines (especially histamines) and proteoglycans (especially heparin). The activation of phospholipase A2 causes the release of membrane lipids followed by development of lipid mediators such as leukotrienes (LTC4, LTD4 and LTE4) and prostaglandins (especially PDG2). There is also secretion of cytokines, the most important of which are TNF-alpha, IL-4 and IL-5. These mediators and cytokines contribute to inflammatory responses. More...
hsa05216	thyroid cancer	Thyroid cancer	Papillary thyroid carcinoma (PTC), the most frequent neoplas...... Papillary thyroid carcinoma (PTC), the most frequent neoplasia originating from the thyroid epithelium, accounts for about 80% of all thyroid cancers. Chimeric oncogenes, created by chromosomal rearrangements involving prevalently RET and, to a less extent, NTRK1 loci, are implicated in the development of papillary carcinoma.These are inappropriately expressed and stimulate constitutive signaling, bypassing the need for receptor activation by growth factors. Alternatively, mutant RAS directly stimulates BRAF, whereas mutant BRAF directly stimulates MEK. Of all thyroid cancers, 15-20% are follicular thyroid carcinoma (FTC). The most distinctive molecular features of follicular carcinoma are the prominence of aneuploidy and the high prevalence of RAS mutations and PAX8-PPAR-gamma rearrangements. The PPAR-gamma rearrangement functions through a dominant-negative effect on the transcriptional activity of wild-type PPAR-gamma. The fusion oncoprotein contributes to malignant transformation by targeting several cellular pathways, some of which are normally engaged by PPAR-gamma. Most poorly differentiated and undifferentiated thyroid carcinomas are considered to derive from pre-existing well-differentiated thyroid carcinoma through additional genetic events, including beta-catenin nuclear accumulation and p53 inactivation, but de novo occurrence might also occur. More...
hsa05020	prion diseases	Prion diseases	Prion diseases, also termed transmissible spongiform encepha...... Prion diseases, also termed transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases that affect humans and a number of other animal species. The etiology of these diseases is thought to be associated with the conversion of a normal protein, PrPC, into an infectious, pathogenic form, PrPSc. The conversion is induced by prion infections (for example, variant Creutzfeldt-Jakob disease (vCJD), iatrogenic CJD, Kuru), mutations (familial CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia (FFI)) or unknown factors (sporadic CJD (sCJD)), and is thought to occur after PrPC has reached the plasma membrane or is re-internalized for degradation. The PrPSc form shows greater protease resistance than PrPC and accumulates in affected individuals, often in the form of extracellular plaques. Pathways that may lead to neuronal death comprise oxidative stress, regulated activation of complement, ubiquitin-proteasome and endosomal-lysosomal systems, synaptic alterations and dendritic atrophy, corticosteroid response, and endoplasmic reticulum stress. In addition, the conformational transition could lead to the lost of a beneficial activity of the natively folded protein, PrPC. More...
hsa04320	dorso ventral_axis_formation	Dorso-ventral axis formation
hsa04662	b cell_receptor_signaling_pathway	B cell receptor signaling pathway	B cells are an important component of adaptive immunity. The...... B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two immunoglobulin (Ig) heavy chains, two Ig light chains and two heterodimers of Ig-alpha and Ig-beta. After BCR ligation by antigen, three main protein tyrosine kinases (PTKs) -the SRC-family kinase LYN, SYK and the TEC-family kinase BTK- are activated. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C-gamma 2 (PLC-gamma 2) are important downstream effectors of BCR signalling. This signalling ultimately results in the expression of immediate early genes that further activate the expression of other genes involved in B cell proliferation, differentiation and Ig production as well as other processes. More...
hsa04666	fc gamma_r_mediated_phagocytosis	Fc gamma R-mediated phagocytosis	Phagocytosis plays an essential role in host-defense mechani...... Phagocytosis plays an essential role in host-defense mechanisms through the uptake and destruction of infectious pathogens. Specialized cell types including macrophages, neutrophils, and monocytes take part in this process in higher organisms. After opsonization with antibodies (IgG), foreign extracellular materials are recognized by Fc gamma receptors. Cross-linking of Fc gamma receptors initiates a variety of signals mediated by tyrosine phosphorylation of multiple proteins, which lead through the actin cytoskeleton rearrangements and membrane remodeling to the formation of phagosomes. Nascent phagosomes undergo a process of maturation that involves fusion with lysosomes. The acquisition of lysosomal proteases and release of reactive oxygen species are crucial for digestion of engulfed materials in phagosomes. More...
hsa04650	natural killer_cell_mediated_cytotoxicity	Natural killer cell mediated cytotoxicity	Natural killer (NK) cells are lymphocytes of the innate immu...... Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit MHC class I exprssion or alter its conformation. The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an adaptive immune response; cytotoxic granules are released onto the surface of the bound target cell, and the effector proteins they contain penetrate the cell membrane and induce programmed cell death. More...
hsa05212	pancreatic cancer	Pancreatic cancer	Normal duct epithelium progresses to infiltrating cancer thr...... Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Pancreatic ductal adenocarcinoma (PDA) show elevated expression of EGF receptors (e.g. HER2/neu) and their ligands (e.g.TGF-alpha) consistent with the presence of this autocrine loop. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway. More...
hsa04914	progesterone mediated_oocyte_maturation	Progesterone-mediated oocyte maturation	Xenopus oocytes are naturally arrested at G2 of meiosis I. E...... Xenopus oocytes are naturally arrested at G2 of meiosis I. Exposure to either insulin/IGF-1 or the steroid hormone progesterone breaks this arrest and induces resumption of the two meiotic division cycles and maturation of the oocyte into a mature, fertilizable egg. This process is termed oocyte maturation. The transition is accompanied by an increase in maturation promoting factor (MPF or Cdc2/cyclin B) which precedes germinal vesicle breakdown (GVBD). Most reports point towards the Mos-MEK1-ERK2 pathway and the polo-like kinase/CDC25 pathway as responsible for the activation of MPF in meiosis, most likely triggered by a decrease in cAMP. More...
hsa04912	gnrh signaling_pathway	GnRH signaling pathway	Gonadotropin-releasing hormone (GnRH) secretion from the hyp...... Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnRHR is coupled to Gq/11 proteins to activate phospholipase C which transmits its signal to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates the intracellular protein kinase C (PKC) pathway and IP3 stimulates release of intracellular calcium. In addition to the classical Gq/11, coupling of Gs is occasionally observed in a cell-specific fashion. Signaling downstream of protein kinase C (PKC) leads to transactivation of the epidermal growth factor (EGF) receptor and activation of mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPK. Active MAPKs translocate to the nucleus, resulting in activation of transcription factors and rapid induction of early genes. More...
hsa05213	endometrial cancer	Endometrial cancer	Two types of endometrial carcinoma are distinguished with re...... Two types of endometrial carcinoma are distinguished with respect to biology and clinical course. Type-I carcinoma is related to hyperestrogenism by association with endometrial hyperplasia, frequent expression of estrogen and progesterone receptors and younger age, whereas type-II carcinoma is unrelated to estrogen, associated with atrophic endometrium, frequent lack of estrogen and progesterone receptors and older age. This classification has also been justified at the molecular level with Type 1 tumours being more commonly associated with abnormalities of DNA-mismatch repair genes, K-ras, PTEN and beta-catenin, and Type 2 tumours with abnormalities of p53 and HER2/neu. More...
hsa04540	gap junction	Gap junction	Gap junctions contain intercellular channels that allow dire...... Gap junctions contain intercellular channels that allow direct communication between the cytosolic compartments of adjacent cells. Each gap junction channel is formed by docking of two 'hemichannels', each containing six connexins, contributed by each neighboring cell. These channels permit the direct transfer of small molecules including ions, amino acids, nucleotides, second messengers and other metabolites between adjacent cells. Gap junctional communication is essential for many physiological events, including embryonic development, electrical coupling, metabolic transport, apoptosis, and tissue homeostasis. Communication through Gap Junction is sensitive to a variety of stimuli, including changes in the level of intracellular Ca2+, pH, transjunctional applied voltage and phosphorylation/dephosphorylation processes. This figure represents the possible activation routes of different protein kinases involved in Cx43 and Cx36 phosphorylation. More...
hsa04722	neurotrophin signaling_pathway	Neurotrophin signaling pathway	Neurotrophins are a family of trophic factors involved in di...... Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory. More...
hsa04960	aldosterone regulated_sodium_reabsorption	Aldosterone-regulated sodium reabsorption	Sodium transport across the tight epithelia of Na+ reabsorbi...... Sodium transport across the tight epithelia of Na+ reabsorbing tissues such as the distal part of the kidney nephron and colon is the major factor determining total-body Na+ levels, and thus, long-term blood pressure. Aldosterone plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct cells localized in the distal nephron, promoting sodium resorption and potassium excretion. Aldosterone enters a target cell and binds MR, which translocates into the nucleus and regulates gene transcription. Activation of MR leads to increased expression of Sgk-1, which phosphorylates Nedd4-2, an ubiquitin-ligase which targets ENAC to proteosomal degradation. Phosphorylated Nedd4-2 dissociates from ENAC, increasing its apical membrane abundance. Activation of MR also leads to increased expression of Na+/K+-ATPase, thus causing a net increase in sodium uptake from the renal filtrate. The specificity of MR for aldosterone is provided by 11beta-HSD2 by the rapid conversion of cortisol to cortisone in renal cortical collecting duct cells. Recently, besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented. More...
hsa04350	tgf beta_signaling_pathway	TGF-beta signaling pathway	The transforming growth factor-beta (TGF-beta) family member...... The transforming growth factor-beta (TGF-beta) family members, which include TGF-betas, activins and bone morphogenetic proteins (BMPs), are structurally related secreted cytokines found in species ranging from worms and insects to mammals. A wide spectrum of cellular functions such as proliferation, apoptosis, differentiation and migration are regulated by TGF-beta family members. TGF-beta family member binds to the Type II receptor and recruits Type I, whereby Type II receptor phosphorylates and activates Type I. The Type I receptor, in turn, phosphorylates receptor-activated Smads ( R-Smads: Smad1, Smad2, Smad3, Smad5, and Smad8). Once phosphorylated, R-Smads associate with the co-mediator Smad, Smad4, and the heteromeric complex then translocates into the nucleus. In the nucleus, Smad complexes activate specific genes through cooperative interactions with other DNA-binding and coactivator (or co-repressor) proteins. More...
hsa04660	t cell_receptor_signaling_pathway	T cell receptor signaling pathway	Activation of T lymphocytes is a key event for an efficient ...... Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells. More...
hsa04012	erbb signaling_pathway	ErbB signaling pathway	The ErbB family of receptor tyrosine kinases (RTKs) couples ...... The ErbB family of receptor tyrosine kinases (RTKs) couples binding of extracellular growth factor ligands to intracellular signaling pathways regulating diverse biologic responses, including proliferation, differentiation, cell motility, and survival. Ligand binding to the four closely related members of this RTK family -epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4)-induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues (pY) within the cytoplasmic tail. Signaling effectors containing binding pockets for pY-containing peptides are recruited to activated receptors and induce the various signaling pathways. The Shc- and/or Grb2-activated mitogen-activated protein kinase (MAPK) pathway is a common target downstream of all ErbB receptors. Similarly, the phosphatidylinositol-3-kinase (PI-3K) pathway is directly or indirectly activated by most ErbBs. Several cytoplasmic docking proteins appear to be recruited by specific ErbB receptors and less exploited by others. These include the adaptors Crk, Nck, the phospholipase C gamma (PLCgamma), the intracellular tyrosine kinase Src, or the Cbl E3 ubiquitin protein ligase. More...
hsa05010	alzheimers disease	Alzheimer's disease	Alzheimer's disease (AD) is a chronic disorder that slowly d...... Alzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. The extracellular Abeta oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Abeta may contribute to pathology by facilitating tau hyper-phosphorylation, disrupting mitochondria function, and triggering calcium dysfunction. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specifically the more amyloidogenic form, Abeta42. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. More...
hsa04370	vegf signaling_pathway	VEGF signaling pathway	There is now much evidence that VEGFR-2 is the major mediato...... There is now much evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells and it is considered to be a crucial signal transducer in both physiologic and pathologic angiogenesis. The binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the binding of VEGF to VEGFR-2 leads to dimerization of the receptor, followed by intracellular activation of the PLCgamma;PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway and subsequent initiation of DNA synthesis and cell growth, whereas activation of the phosphatidylinositol 3' -kinase (PI3K)-Akt pathway leads to increased endothelial-cell survival. Activation of PI3K, FAK, and p38 MAPK is implicated in cell migration signaling. More...
hsa04010	mapk signaling_pathway	MAPK signaling pathway	The mitogen-activated protein kinase (MAPK) cascade is a hig...... The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli. More...

MAPK1 related BioCarta pathways (count: 40)

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
BIOPEPTIDES_PATHWAY	biopeptides pathway	Bioactive Peptide Induced Signaling Pathway	Many different peptides act as signaling molecules, includin...... Many different peptides act as signaling molecules, including the proinflammatory peptide bradykinin, the protease enzyme thrombin, and the blood pressure regulating peptide angiotensin. While these three proteins are distinct in their sequence and physiology, and act through different cell surface receptors, they share in a common class of cell surface receptors called G-protein coupled receptors (GPCRs). Other polypeptide ligands of GPCRs include vasopressin, oxytocin, somatostatin, neuropeptide Y, GnRH, leutinizing hormone, follicle stimulating hormone, parathyroid hormone, orexins, urotensin II, endorphins, enkephalins, and many others. GPCRs are a broad and diverse gene family that respond not only to peptide ligands but also small molecule neurotransmitters (acetylcholine, dopamine, serotonin and adrenaline), light, odorants, taste, lipids, nucleotides, and ions. The main signaling mechanism used by GPCRs is to interact with G-protein GTPase proteins coupled to downstream second messenger systems including intracellular calcium release and cAMP production. The intracellular signaling systems used by peptide GPCRs are similar to those used by all GPCRs, and are typically classified according to the G-protein they interact with and the second messenger system that is activated. For Gs-coupled GPCRs, activation of the G-protein Gs by receptor stimulates the downstream activation of adenylate cyclase and the production of cyclic AMP, while Gi-coupled receptors inhibit cAMP production. One of the key results of cAMP production is activation of protein kinase A. Gq-coupled receptors stimulate phospholipase C, releasing IP3 and diacylglycerol. IP3 binds to a receptor in the ER to cause the release of intracellular calcium, and the subsequent activation of protein kinase C, calmodulin-dependent pathways. In addition to these second messenger signaling systems for GPCRs, GPCR pathways exhibit crosstalk with other signaling pathways including tyrosine kinase growth factor receptors and map kinase pathways. Transactivation of either receptor tyrosine kinases like the EGF receptor or focal adhesion complexes can stimulate ras activation through the adaptor proteins Shc, Grb2 and Sos, and downstream Map kinases activating Erk1 and Erk2. Src kinases may also play an essential intermediary role in the activation of ras and map kinase pathways by GPCRs. More...
SPPA_PATHWAY	sppa pathway	Aspirin Blocks Signaling Pathway Involved in Platelet Activation	Activation of the protease-activated GPCRs in platelets cont...... Activation of the protease-activated GPCRs in platelets contributes to platelet activation in clotting. The protease-activated receptors PAR1 and PAR4 are cleaved by the protease thrombin, releasing a tethered peptide ligand that activates the receptor and triggers intracellular calcium release. Platelets from mice lacking the PAR4 gene are not activated by thrombin and are impaired in clotting, supporting the importance of thrombin signaling through PAR4 in clotting. Human platelets express both PAR1 and PAR4, with PAR1 playing a more dominant role in clotting in humans. Calcium release induced by PARs activates PKC, modulating integrin alpha IIB beta 3 (glycoprotein IIb/IIIa) and opening integrin ligand binding sites to contribute to platelet aggregation. Intracellular calcium increases induced by thrombin activates phospholipase A2, liberating arachidonic acid, the first step in prostaglandin and thromboxane biosynthesis. Ras/Map kinase activation by the PAR receptors also activates phospholipase A2. The activation of PAR-induced platelet aggregation is inhibited by aspirin, indicating that thromboxane production induced by PAR signaling contributes to platelet activation. Arachidonic acid is converted to the prostaglandin PGG2 by the enzyme Cox-1 in platelets, and Cox-1 is inhibited by aspirin, reducing thromboxane A2 production by platelets. Thromboxane is a potent vasoconstrictor and platelet activator, so inhibition of Cox-1 in platelets by aspirin may explain some of the cardioprotective actions of aspirin. More...
ERK_PATHWAY	erk pathway	Erk1/Erk2 Mapk Signaling pathway	The p44/42 MAP Kinase pathway consists of a protein kinase c...... The p44/42 MAP Kinase pathway consists of a protein kinase cascade linking growth and differentiation signals with transcription in the nucleus. Growth factor receptors and tyrosine kinases activate Ras which in turn activates c-Raf, MEK, and MAP kinase. Activated p44/42 MAP Kinase translocates to the nucleus and activates transcription by phosphorylation of kinases such as p90 RSK, MSK, and transcription factors such as ELK-1 and Stat3. The importance of this pathway in both growth control and development has been demonstrated via the transforming properties of various mutant forms of Ras, Raf, MEK and by their effects on development. Signal amplification and the potential for crosstalk appear to be important features of this regulatory network. More...
PPARA_PATHWAY	ppara pathway	Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha)	The most recognized mechanism by which peroxisome proliferat...... The most recognized mechanism by which peroxisome proliferators regulated gene expresssion is through a PPAR/RXR heterodimeric complex binding to a peroxisome proliferator-response element (PPRE) (classical mechanism). However, there are the possibility of several variations on this theme: 1). The peroxisome proliferator interacts with PPAR that preexists as a DNA complex with associated corepressors proteins. The interaction with ligand causes release of the corepressor and association with a coactivator, resulting in the classical mechanism. 2). The peroxisome proliferator interacts with PPAR as a soluble member of the nucleus. The binding of ligand results in RXR heterodimerization, DNA binding and coactivator recruitment. 3). In this scenario, PPAR exists in the cytosol, perhaps complexed to heat shock protein 90 and/or other chaperones. Binding of peroxisome proliferator causes a conformational change and translocation into the nucleus. Scenarios 4 and 5 require regulation of gene expression via non-classical mechanisms: 4). PPAR is capable of interacting with, and forming DNA binding heterodimers with, several nuclear receptors including the thyroid hormone receptor. The binding site for this non-RXR heterodimer need not be the classic DR-1 motif found in the PPRE. 5). PPAR may participate in the regulation of gene expression witout binding to DNA. By association with transcription factors such as c-jun or p65, PPAR diminishes the ability of AP1 or NFB to bind to their cognate DNA sequences, respectively. Also shown in this scheme are two means to modify the peroxisome proliferator response. Most importantly, growth factor signaling has a pronounced affect on PPAR via post-translational modification. PPAR is a phosphoprotein and its activity is affected by insulin. Several kinase pathways affects PPARa's activity, although the specific kinases and phosphorylation sites have not been conclusively determined. More...
BARRESTIN_SRC_PATHWAY	barrestin src_pathway	Roles of fl-arrestin-dependent Recruitment of Src Kinases in GPCR Signaling	The binding of -arrestins to agonist-occupied GPCRs coincide...... The binding of -arrestins to agonist-occupied GPCRs coincides with the recruitment of Src family tyrosine kinases, including c-Src, Hck and c-Fgr (Src-TK), to the receptor-arrestin complex. Several signaling events have been reported to involve -arrestin-dependent Src recruitment. These include the regulation of clathrin-dependent 2-adrenergic receptor endocytosis by tyrosine phosphorylation of dynamin, Ras-dependent activation of the ERK1/2 MAP kinase cascade and stimulation of cell proliferation by 2-adrenergic and neurokinin NK1 receptors, and stimulation of chemokine CXCR1 receptor-mediated neutrophil degranulation More...
KERATINOCYTE_PATHWAY	keratinocyte pathway	Keratinocyte Differentiation	The epidermis, which provides a protective barrier that unde...... The epidermis, which provides a protective barrier that undergoes a constant renewal, is a multi-layered tissue with the proliferating cells located in the basal layer. As cells leave the basal layer the underog significant differentiation, biochemical and morphological remodeling. The final differentiation results in the formation of corneocytes. In vitro keratinocytes mimic this process. Several genes mark keratinocyte specific differentiation. Among the most frequently tracked markers are Transglutaminase, Cystatin and Involucrin. The keratinocyte differentiation studies have identified and provided significant detail regarding the involvement of three of the 4 major MAP kinase pathways from several diverse stimuli such as EGF, FAS, TNF and Calicium influx. The p38 cascade is represented twice since both p38alpha (p38) and p38delta (MAPK13) are involved. The keratinocyte differentiation cascased also provide for detailed study of the functions of individual PKC isoforms. It is interesting to note the contrasting functions of the PKC isoforms in this process. In recent studies it has been determined that the cPKC (conventional/classical Protein Kinase C) isoforms, which are calcium-, phospholipid-, and diacylglycerol-dependent are inhibitory where as the nPKC (novel Protein Kinase C) isoforms which are calcium independent are stimulatory for keratinocyte differentiation markers. On the right hand side is an earlier step showing the upregulation loop of TRAF2. This step occurs prior to the activation os ASK1 and the p38 cascade. More...
EIF4_PATHWAY	eif4 pathway	Regulation of eIF4e and p70 S6 Kinase	eIF-4F and p70 S6 kinase play critical roles in translationa...... eIF-4F and p70 S6 kinase play critical roles in translational regulation. eIF-4F is a complex whose functions include the recognition of the mRNA 5' cap structure (eIF-4E), delivery of an RNA helicase to the 5' region (eIF-4A), bridging of the mRNA and the ribosome (eIF-4G), and circularization of the mRNA via interaction between eIF-4G and the poly(A) binding protein (PABP). Several stimuli, including growth factors and cytokines, regulate the eIF-4 complex and p70 S6 kinase by initiating a phosphorylation cascade involving the sequential activation of PI3-K, PDK1/2, Akt/PKB, and FRAP/mTOR kinase. FRAP/mTOR, together with an unidentified kinase, phosphorylates 4E-BP, leading to its dissociation from and activation of eIF-4E. MNK1/2, activated by ERK and p38 MAPK, phosphorylates and activates eIF-4E. Both processes contribute to the association of eIF-4E and eIF-4G to form the active eIF-4F complex, a necessary component of the 48S initiation complex. Phosphorylation of ribosomal protein S6 by p70 S6 kinase stimulates the translation of mRNAs with a 5' oligopyrimidine tract which typically encode components of the protein synthesis. More...
CCR3_PATHWAY	ccr3 pathway	CCR3 signaling in Eosinophils	Eosinophils are a key class of leukocytes involved in inflam...... Eosinophils are a key class of leukocytes involved in inflammatory responses, including allergic reactions in skin and airway. The eosinophil response in inflammation is absent in mice lacking CCR3, indicating the key role of this G protein coupled receptor in inflammation and allergic responses. Eotaxin is a chemokine ligand for CCR3 that recruits eosinophils to the site of inflammation and activates them. Other chemokine ligands of CCR3 include eotaxin-2, MCP-3, MCP-4, and RANTES. Multiple signaling pathways activated by CCR3 participate in the inflammatory response of eosinophils. Eotaxin stimulates intracellular calcium release, production of reactive oxygen species, and changes in actin polymerization through a pertussis sensitive pathway. Rho and ROCK regulate actin stress fiber formation and are required for eosinophil chemotaxis. Rho is a G protein that activates ROCK, a protein kinase. Map kinase pathways are also involved in chemotaxis. Another key action of activated eosinophils is the release of reactive oxygen species, causing tissue damage during chronic inflammatory responses. Blocking eosinophil activation and the signaling pathways that lead to chemotaxis, degranulation and reactive oxygen release may alleviate inflammatory conditions and inflammation-associated tissue damage. More...
IGF1R_PATHWAY	igf1r pathway	Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation	IGF-1R, the type 1 receptor for insulin-like growth factor, ...... IGF-1R, the type 1 receptor for insulin-like growth factor, mediates cell survival and growth in response to its ligands IGF-1 and IGF-2. This tyrosine kinase receptor is widely expressed in many cell types and is a key mediator of growth. Overexpression or activation of IGF-1R may be involved in the proliferation of transformed cells, making inhibition of IGF-1R signaling a strategy for the development of cancer drugs. IGF-1R activates three signaling pathways that converge to phosphorylate BAD protein and block apoptosis. The first pathway activated by IGF-1R stimulates PI3-kinase and the AKT pathway to phosphorylate BAD and block apoptosis. A second pathway activated by IGF-1R involves ras mediated activation of the map kinase pathway to block apoptosis. A third pathway involves interaction of raf with mitochondria in response to IGF-1R activation. The convergence of these pathways to block apoptosis may enhance the IGF-1R response. More...
FCER1_PATHWAY	fcer1 pathway	Fc Epsilon Receptor I Signaling in Mast Cells	The Fc Epsilon Receptor 1 signaling pathway in mast cells us...... The Fc Epsilon Receptor 1 signaling pathway in mast cells uses multiple core signal path to achieve its necessary ends. Through the BTK protein and PKC Mast cells are able to degranulate, through the PKC and MAPK paths the cells are able to alter cytokine expression and arachidonic acid release. More...
MCALPAIN_PATHWAY	mcalpain pathway	mCalpain and friends in Cell motility	The mammalian calpain gene family currently contains 13 dist...... The mammalian calpain gene family currently contains 13 distinct large subunit products most of which complex with one of two smaller 30kDa subunits. ( An excellent introduction to the calpain family can be found on a web site created by Valery Thompson http://ag.arizona.edu/calpains/index.html ) One of the most carefully studied functions of the calpains is the regulation of integrin-mediated cell migration. Calpains digests the links between the actin cytoskeleton and several focal adhesion complex proteins; talin, paxillin and focal adhesion kinase. The release from the focal adhesion complex facilitates migration. Calpestatin is an inhibitor expressed in most cells. Calpestatin binds the four inhibitory domains of calpain. Release from calpestatin does not activate calpain. Activation requires additional signaling, coactivators and an appropriate calcium concentration. During cell migration calpain1 (mu-calpain) acts at the leading edge as a response to integrin signals or calcium fluxuations due to the stretch activated calcium channels. Calpain1 cleaves the target proteins, talin, exzrin, paxillin and the cytoplasmic tail of the integrins B1(a) and B3(b) to release the adhesion and form new adhesions. Calpain2 (M-calpain) is believed to be membrane bound and functions at the trailing edge of the migrating cell to cleave the integrins in response to growth factor receptor signals. PKA functions to down regulate or inhibit calpain2. Disease related notes: In Alzheimers disease, amyloid peptides interfere with calpain activity causing a mislocalization of cdk5. Deregulated cdk5 hyperphosphorylates tau promoting cell death in neurons. Mutations in the muscle specific calpain p94 lead to Limb Girdle muscular dystrophy 2A (LGMD2A). Over activity of calpains due to elevated calcium leads to tissue damage in the heart and brain More...
EDG1_PATHWAY	edg1 pathway	Phospholipids as signalling intermediaries	Sphingosine-1-phosphate (S1P) is an example of lipid messeng...... Sphingosine-1-phosphate (S1P) is an example of lipid messengers with both intracellular and extracellular functions. Intracellularly S1P regulates proliferation and survival; extracellularly S1P is a ligand for EDG1 (also known as S1P1). Activation of sphingosine kinase (SPHK), the enzyme that catalyzes the phosphorylation of sphingosine, increases cellular levels of S1P. Inhibitors of SPHK block formation of S1P and inhibit cellular proliferation induced by a variety of factors, including as an example platelet-derived growth factor (PDGF) and PMA. In a study using endothelial cells it was demonstrated that S1P induces activation of alpha-v and B3 integrins via RhoA. S1P also activates Akt via Gi and PI3K. The activated Akt phosphorlyates the Edg1 receptor on threonine 236 leading to the activation of Rac1 and subsequent signals leading to actin assembly, chemotaxis and lamellipodia formation. Edg1 stimulation also leads to the activation of the ERK signaling cascade resulting in anti-apoptotic reversal, proliferation and cell survival. More...
MAL_PATHWAY	mal pathway	Role of MAL in Rho-Mediated Activation of SRF	Serum response factor (SRF) is a transcription factor, which...... Serum response factor (SRF) is a transcription factor, which binds to a serum response element (SRE) associated with a variety of genes including (i)immediate early genes such as c-fos, fosB, junB, egr-1 and -2, (ii)neuronal genes such as nurr1 and nur77, and (iii)muscle genes such as actins and myosins. By regulating expression of these genes, SRF controls cell growth and differentiation, neuronal transmission as well as muscle development and function. SRF can be activated by serum, lysophosphatidic acid (LPA), lipopolysaccharide (LPS), 12-O-tetradecanoylphorbol-13-acetate (TPA), cytokines, tumor necrosis factor-alpha (TNFalpha), agents that increase intracellular Ca2+, T-cell virus1 activator protein, hepatitis B virus activator proteins pX, activated oncogenes and protooncogenes and extracellular stimuli such as antioxidant and UV light. In serum-starved cells, MAL is predominantly cytoplasmic where it is sequestered by actin monomers. Upon serum stimulation, Rho becomes active and, through its interaction with ROCK and mDia1, causes an accumulation of F-actin and a commensurate decrease in the level of G-actin. As a consequence, MAL is no longer sequestered and is free to translocate to the nucleus where it associates with SRF and activates SRE-mediated gene expression. More...
CXCR4_PATHWAY	cxcr4 pathway	CXCR4 Signaling Pathway	CXCR4 is a chemokine receptor in the GPCR gene family, and i...... CXCR4 is a chemokine receptor in the GPCR gene family, and is expressed by cells in the immune system and the central nervous system. In response to binding its ligand SDF-1 (stromal cell-derived factor-1), CXCR4 triggers the migration and recruitment of immune cells. This ligand-receptor pair may also play a role in development of the nervous system. In addition to acting as a chemokine receptor, CXCR4 is a co-receptor for entry of HIV into T cells and ligands of CXCR4, including SDF-1 may help to block HIV infection. Early in the infection of an individual, HIV viruses often are tropic for the CCR5 coreceptor that provides for macrophage entry, then later in infection are tropic for CXCR4 and T cell entry. Viruses that are tropic for CXCR4 are generally syncitium forming, causing T cells to aggregate and be destroyed at a rapid rate. CXCR4 induces downstream signaling by several different pathways. As a GPCR, CXCR4 binding of SDF-1 activates G-protein mediated signaling, including downstream pathways such as ras, and PI3 kinase. PI3 kinase activated by SDF-1 and CXCR4 plays a role in lymphocyte chemotaxis in response to these signals. One endpoint of CXCR4 signaling is the activation of transcription factors such as AP-1 and chemokine regulated genes. JAK/STAT signaling pathways also appear to play a role in SDF-1/CXCR4 signaling. Delineation of the signaling mechanisms utilized by CXCR4 may assist in determining the role of CXCR4 in HIV infection and in the immune response. More...
NFAT_PATHWAY	nfat pathway	NFAT and Hypertrophy of the heart (Transcription in the broken heart)	Hypertrophy associated with both hypertension and obstructio...... Hypertrophy associated with both hypertension and obstruction to ventricular outflow leads to pathologic cardiac growth and it is associated with increase morbidity and mortality. Symptomatic ventricular disease takes a growing toll on the health of nations. As other cardiovascular diseases such as stroke and myocardial infraction are in decline as causes of mortality, the heart failure problem becomes increasingly urgent. Congenital heart defects occur in 1% of live births and fetal heart malformations are implicated in many pregnancies that end in still-birth or spontaneous abortion. The current paradigm suggests that the heart adapts to excess of hemodynamic loading by compensatory hypertrophy, which under condition of persistent stress, over time evolves into dysfunction and myocardial failure. There is considerable evidence that direct effects of increased mechanical stress are sensed within the ventricular wall and that signals critical for the generation of growth responses. Despite compelling statistics we still do not understand biochemically why heart defects are so prevalent. A single transcriptional regulator initially associated with the activation of the T-cells More...
AGR_PATHWAY	agr pathway	Agrin in Postsynaptic Differentiation	The heparan sulphate proteoglycan agrin is well known as the...... The heparan sulphate proteoglycan agrin is well known as the key assembly factor of postsynaptic differentiation at the neuromuscular junction (NMJ), but recent data suggest it also plays a direct role in the organization of the cytoskeleton in the skeletal muscle. Signaling through muscle-specific proteins such as muscle specific kinase (MuSK) and or acetylcholine receptor (AchRs)/rapsyn, agrin can activate ubiquitously expressed Rac, Cdc42, and p21-activated kinase (PAK) that are involved in actin polymerization. Agrin also engages signaling pathways of several potent oncogenes (i.e., SFK, ErbB receptors, and cortactin). More...
HCMV_PATHWAY	hcmv pathway	Human Cytomegalovirus and Map Kinase Pathways	To replicate in the host cell, viruses commandeer cellular s...... To replicate in the host cell, viruses commandeer cellular signaling pathways. Cytomegalovirus (CMV) is a DNA virus with that is widespread in the population but usually causes disease only in immunocompromised individuals and is also a viral cause of birth defects. One of the actions of CMV in the host cell is to stimulate MAP kinase pathways. Both p38 and ERK kinases are activated by CMV infection through activation map kinase kinases and inhibition of phosphatases. One result of Map kinase activation by CMV is activation of transcription of viral genes, increasing the production of viral gene products. Both p38 and ERK kinases contribute to the activation of viral genes by cellular transcription factors acting through the viral UL4 promoter at upstream and basal transcription elements. Another target of prolonged p38 activation during infection is Rb, contributing to viral replication. Activation of MKK1 and MKK2 leads to Erk1 and Erk2 activation, and phosphorylation of downstream targets. The MEKK1 kinase regulates the immediate early promoter indirectly through downstream kinase signaling and perhaps more directly through activation of NF-kB. Map kinase pathways activated by CMV converge on increased transcription of viral genes and increased replication of the viral genome. Better understanding of the mechanisms involved in the interaction of CMV with cellular signaling machinery will provide improved ways to treat CMV-mediated disease. More...
IL2RB_PATHWAY	il2rb pathway	IL-2 Receptor Beta Chain in T cell Activation	The IL-2 receptor is a key component of immune signaling and...... The IL-2 receptor is a key component of immune signaling and is required for the activation, proliferation, and survival of T cells. This receptor is composed of three polypeptide chains, the alpha, beta and gamma chains. The IL-2 receptor gamma chain is a common component for several other cytokine receptors, including IL-4, IL-7, IL-9 and IL-15. The IL-2 receptor beta chain is essential for IL-2 signaling and is also a component of the IL-15 receptor complex. The polypeptides of the IL-2 receptor do not themselves have intrinsic catalytic activity, but interact with cytoplasmic signaling proteins to transduce signals. br>Different regions of the cytoplasmic domain of the IL-2 receptor beta chain interact and couple with distinct signaling pathways and cellular responses. JAK1 associates with the beta chain, and JAK3 with the gamma chain. Binding of IL-2 induces heterodimerization of receptor subunits, and activation of JAK kinase activity. Tyrosine residues in the beta chain cytoplasmic domain are phosphorylated during activation, recruiting other factors to the phosphorylated tyrosine residues through src homology 2 (SH2) domains. The adaptor protein Shc binds to phosphorylated tyrosine 338 of the beta chain. When bound, Shc is phosphorylated and couples through Grb2 and Sos-1 to activate Ras and stimulate T cell proliferation. Another key proliferative pathway activated by IL-2 is phosphorylation of STAT-5 by JAK kinases. STAT-5 is recruited to IL-2 beta phosphorylated tyrosines at multiple positions, including Y338, Y392 and Y510. Once phosphorylated, STAT-5 enters the nucleus to regulate the transcription of several genes, some proliferative such as cyclin genes and others that are involved in T cell immune function such as cytokine genes. The suppressors of cytokine activation, SOCS-3 and SOCS-1, oppose phosphorylation and activation of STAT-5 and JAK1 caused by IL-2. PI3 kinase is another protein recruited to IL-2 receptor beta chain tyrosines when phosphorylated. Activation of PI3 Kinase also contributes to the proliferative activity of IL-2 in T cells. The role of other tyrosines in the IL-2 receptor beta chain, Y355, Y358 and Y361, is not yet clear, but may be involved in signaling by the protein kinase p56lck. In addition to stimulating T cell activation and proliferation, IL-2 activation blocks T cell apoptosis through multiple pathways. Among the genes activated by STAT-5 are BCL-xL, an inhibitor of apoptosis, and fas-ligand, an activator of apoptosis in cells expressed the fas receptor. PI3 kinase also contributes to anti-apoptotic activity of IL-2 through AKT activation. T cell responses to IL-2 must be coordinated in part in the complex protein-protein interactions with the IL-2 receptor beta chain. More...
MPR_PATHWAY	mpr pathway	How Progesterone Initiates Oocyte Membrane	Progesterone (Pg) binds to both intracellular iPR and plasma...... Progesterone (Pg) binds to both intracellular iPR and plasma membrane- bound mPR. (Right Top) After binding to Pg, iPR is recruited to the membrane associated protein tyrosine kinase p60c- src, which induces activation of the MAPK signaling pathway. This results in activation of p90Rsk and the subsequent phosphorylation and inactivation of Myt1, which favors formation of the activated cell cycle complex cyclin B-Cdc2. Activation of cyclin B-Cdc2 causes breakdown of the germinal vesicle and the initiation of oocyte maturation. (Left). In contrast, binding of Pg to mPR leads to inhibition of adenylyl cyclase (AC) through activation of Gi or inhibition of Gs. This leads to a decrease in the cAMPdependent kinase PKA, which relieves inhibition of Cdc25C (the phosphatase that dephosphorylates and activates cyclin B-Cdc2) and also indirectly promotes the activation of MAPK signaling. PKA also regulates the initiation of oocyte maturation through other effects that are independent of PKA activity. More...
GH_PATHWAY	gh pathway	Growth Hormone Signaling Pathway	Growth hormone plays a major role in regulating growth durin...... Growth hormone plays a major role in regulating growth during childhood and adolescence and also regulates metabolism. Defects in growth hormone signaling can result in dwarfism and decreases in growth hormone levels with age have been suggested to play a role in the reduced function of some physiological systems. Growth hormone signals a response in cells through the growth hormone receptor, a member of the cytokine receptor gene family. Growth hormone causes the receptor to dimerize, activating the JAK2 protein kinase. The activity of JAK2 mediates many of the downstream responses to growth hormone through phosphorylation of STAT transcription factors, MAP kinases, other kinase cascades and molecules involved in metabolism like IRS-1. Factors like SOCS and SHP-1 appear to play a role in the down regulation of signaling by growth hormone and cytokines. More...
ECM_PATHWAY	ecm pathway	Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal Epithelia	Activation of the MAPK kinase pathway has been identified as...... Activation of the MAPK kinase pathway has been identified as a mechanism that integrins use to regulate gene expression leading to cell shape changes during cell spreading or migration Epithelial cells respond to extracellular matrix (ECM) cause integrin-mediated FAK phosphorylation that in turn phosphorylates the surrounding proteins (paxillin, Fyn/shc, and src) and leads to signal amplification. FAK also binds PI-3 kinase and is upstream of the MAP kinase pathway. When MAPkinase or PI-3 kinase was inhibited, actin reorganization was blocked. Src phosphorylates p190RhoGAP, inactivating its GAP function that may allow RhoGTP to stay active longer, promoting further signal amplification. Activated RhoGTP binds to downstream kinases such as Rho-associated coiled coil-containing protein kinase (p160ROCK) and p140 diaphanous (p140Dia) to increase actin polymerization and contraction. Actin reorganization assists integrin clustering, allowing more ECM binding that increase FAK phosphorylation and other signal transduction events. More...
PTEN_PATHWAY	pten pathway	PTEN dependent cell cycle arrest and apoptosis	PTEN is a tumor suppressor gene. Recombinant PTEN is capable...... PTEN is a tumor suppressor gene. Recombinant PTEN is capable of dephosphorylating phosphatidylinositol 3,4,5-triphosphate, the product of phosphatidylinositol 3 -kinase. Many of the cancer-related mutations have been mapped to the phosphatase catalytic domain, it has been suggested that the phosphatase activity of PTEN is required for its tumor suppressor function. The activation of PKB/AKT is regulated in a complex manner via phosphorylation of AKT on Thr308 and Ser473 by PDK1 and ILK(integrin-linked kinase) respectively. Inactivation of PTEN will constitutively activate PKB/AKT pathway. In addition to its role in regulating the PI 3-K/AKT cell survival pathway, PTEN also inhibits growth factor-induced Shc phosphorylation and suppresses the mitogen-activated protein (MAP) kinase signaling pathway. PTEN also interact with FAK, a key molecule implicated in integrin signaling pathways, and it directly dephosphorylates tyrosine-phosphorylated FAK. PTEN down-regulation of p130CAS through FAK results in inhibition of cell migration and spreading. More...
MET_PATHWAY	met pathway	Signaling of Hepatocyte Growth Factor Receptor	The hepatocyte growth factor receptor, also called c-Met, is...... The hepatocyte growth factor receptor, also called c-Met, is activated by HGF and stimulates proliferation of hepatocytes and other cell types. Mutated forms of the HGF receptor are associated with oncogenesis and metastasis, making the HGF receptor a potential therapeutic target for cancer drugs. Changes in cell motility, cell shape, adhesion, resistance to apoptosis, and anchorage independent growth all contribute to the role of c-Met in cancer. The HGF receptor is a heterodimer with tyrosine kinase activity and associates with a multiprotein complex involved in downstream signal transduction. The HGF receptor can associate with several different signaling systems, including src, Grb2/SOS, PI3 kinase and Gab1. One of the major substrates of the activated HGF receptor tyrosine kinase is the adaptor protein Gab1. Gab1 interacts with Crk and CrkL, two proteins with SH2 and SH3 protein interaction domains that couple to signaling further downstream. The actions of HGF on paxillin, DOCK180 and Rap1 mediated through GAB1 and other members of this complex alter cell motility. Regulation of Rho, Rac1 and CDC42 pathways in response to HGF all contribute to changes in cellular motility. Another target of the HGF receptor kinase is the focal adhesion kinase, FAK. The activation of FAK induces the formation of focal adhesions, a preliminary step to increased cell motility and tissue invasion by transformed cells, and paxillin phosphorylation may also alter cell adhesion of Met transformed cells. Src and p130cas are required for the role of FAK in HGF induced cellular transformation. HGF also blocks anoikis, the induction of apoptosis through suspension of cells, by acting on Erk and AKT kinases. This activity may contribute to anchorage independent growth of Met transformed cells. Signaling by integrins also plays a key role in the activation of tissue invasive growth by HGF. The alpha6beta4 integrin acts as a cofactor along with Meta to participate in cell growth and proliferation. In addition to altering cell adhesion, proliferation and cell motility, HGF alters cellular transcription through activation of STAT3. STAT3 activation by HGF is independent of PI3 kinase or map kinases and alters gene expression leading to changes in cellular shape. Although HGF is associated with cellular proliferation and survival, in rat liver epithelial cells HGF induces apoptosis and inhibits cell growth. More...
INTEGRIN_PATHWAY	integrin pathway	Integrin Signaling Pathway	Integrins are cell surface receptors that interact with the ...... Integrins are cell surface receptors that interact with the extracellular matrix and mediate intracellular signals in response to the extracellular matrix including cellular shape, mobility, and progression through the cell cycle. Integrins do not themselves possess a kinase domain or enzymatic activity but rely on association with other signaling molecules to transmit signals. Interactions between the extracellular matrix and the actin cytoskeleton commonly take place at focal adhesions on the cell surface that contain localized concentrations of integrins, signaling molecules, and cytoskeletal elements. Talin forms a direct interaction with the integrin cytoplasmic domain, and interacts with cytoskeletal elements (actin) and signaling factors. Paxillin and CAS also localize in focal adhesions and may serve as a scaffold for other integrin signaling components like FAK and src. Interaction of FAK, CAS and src may be required for integrin regulation of cell cycle progression. The CrkL adaptor protein may regulate downstream integrin signaling. Growth factor signaling pathways and the caveolin receptor exhibit important cross talk with integrin receptors in cellular responses like activation of map kinase, proliferation and motility. More...
CREB_PATHWAY	creb pathway	Transcription factor CREB and its extracellular signals	The transcription factor CREB binds the cyclic AMP response ...... The transcription factor CREB binds the cyclic AMP response element (CRE) and activates transcription in response to a variety of extracellular signals including neurotransmitters, hormones, membrane depolarization, and growth and neurotrophic factors. Protein kinase A and the calmodulin-dependent protein kinases CaMKII stimulate CREB phosphorylation at Ser133, a key regulatory site controlling transcriptional activity. Growth and neurotrophic factors also stimulate CREB phosphorylation at Ser133. Phosphorylation occurs at Ser133 via p44/42 MAP Kinase and p90RSK and also via p38 MAP Kinase and MSK1. CREB exhibit deficiencies in spatial learning tasks, while flies overexpressing or lacking CREB show enhanced or diminished learning, respectively. More...
CDK5_PATHWAY	cdk5 pathway	Phosphorylation of MEK1 by cdk5/p35 down regulates the MAP kinase pathway	Map kinases transduce responses to extracellular signals by ...... Map kinases transduce responses to extracellular signals by a variety of routes, and communicate with other pathways through extensive crosstalk networks. A closely studied Map kinase cascade originates with tyrosine kinase activation, and activation of Ras. Ras activates Raf, Raf activates the Map kinase kinases Mek1 and Mek2 and these kinases activate downstream Map kinases like Erk1 and Erk2. Erk1 and Erk2 in turn activate transgenes like p35 through the Map kinase activated transcription factor EGR-1. Mek1 plays a central role in many different Map kinase pathways. Factors that activate Mek1 include growth factors like NGF, cytokines, chemokines, and phorbol ester, resulting in cellular proliferation and survival. Mek1 activation may also play a role in differentiation in neuronal tissues. In cultured neuronal PC-12 cells, NGF induces neurite outgrowth via Mek1 and the map kinase pathway. Constitutive activation of Mek1 can transform cells and may play a role in cancer. The crucial role of Mek1 in a variety of pathways including cellular transformation suggests that the cell must tightly regulate its activity. Cdk5 is a kinase that regulates the activity of Mek1. Although Cdk5 is a member of the cyclin-dependent kinase gene family, the activity of Cdk5 does not appear to be regulated by cyclins, but is activated by association with p35. Cdk5 does not act as a checkpoint kinase to regulate cell cycle progression, but acts as a regulatory kinase involved in other post-mitotic processes such as neuronal activity such as neuronal migration during development and neurite outgrowth. Mice lacking Cdk5 exhibit defects in neuronal development. One target of Cdk5 is Mek1. Phosphorylation of Mek1 by Cdk5 represses Mek1 activity and blocks downstream cellular responses. The activation of p35 by Map kinase pathways followed by deactivation of Map kinase signaling by the Cdk5/p35 complex completes the loop of a feedback circuit to terminate Map kinase signaling. More...
BAD_PATHWAY	bad pathway	Regulation of BAD phosphorylation	The function of the pro-apoptotic molecule BAD is regulated ...... The function of the pro-apoptotic molecule BAD is regulated by phosphorylation of three sites (ser 112,136 and 155). Phosphorylation at these sites results in loss of the ability of BAD to heterodimerize with the survival proteins BCL-XL or BCL-2. Phosphorylated BAD binds to 14-3-3 and is sequestered in the cytoplasm. While ser-136 phosphorylation is concordant with the activation of Akt, Ser-112 phosphorylation requires activation of the Ras-MAPK pathway. BAD Ser 155 was found to be a major site of phosphorylation induced following stimulation by growth factors and prevented by protein kinase A inhibitors. More...
ARENRF2_PATHWAY	arenrf2 pathway	Oxidative Stress Induced Gene Expression Via Nrf2	Reactive oxygen species (ROS) can damage biological macromol...... Reactive oxygen species (ROS) can damage biological macromolecules and are detrimental to cellular health. Electrophilic compounds, xenobiotics and antioxidants are sources of reactive oxygen species, creating oxidative stress that can harm cells. Enzymes are involved in the Phase II detoxification of xenobiotics to reduce cellular stress include glutathione transferases, quinone reductase, epoxide hydrolase, heme oxygenase, UDP-glucuronosyl transferases, and gamma-glutamylcysteine synthetase. Expression of these genes protects cells from oxidative damage and can prevent mutagenesis and cancer. Transcription of these enzymes is coordinately regulated through antioxidant response elements (AREs). Nrf2 (NF-E2-related factor 2) and Nrf1 are transcription factors that bind to AREs and activate these genes. Inactive Nrf2 is retained in the cytosol by association a complex with the cytoskeletal protein Keap1. Cytosolic Nrf2 is phosphorylated and translocates into the nucleus in response to protein kinase C activation and Map kinase pathways. In the nucleus, Nrf2 activate genes through AREs by interacting with transcription factors in the bZIP family, including CREB, ATF4 and fos or jun. Nrf2 activation of genes is opposed by small maf proteins, including MafG and MafK, maintaining a counterbalance to Nrf2 and balancing the oxidation level of the intracellular environment. More...
PYK2_PATHWAY	pyk2 pathway	Links between Pyk2 and Map Kinases	This diagram is a compilation of Pyk2 effort cascades. In sp...... This diagram is a compilation of Pyk2 effort cascades. In specific cell types the receptor and effoectors will vary. Binding of a transmembrane receptor triggers the activation of Ca2+ signaling and PKC. The signal is then transmitted to Pyk2 and further to the small G protein Rac1. In turn, Rac1 initiatates the JNK cascade, starting with PAK follwed by MEKK1, SEK1, and JNK. JNK activation causes induction of c-Jun gene binding. Pyk2 stimulation has also been shown to activate MKK3 leading to activation of p38. The other major mitogen activated kinase cascade for ERK1/2 is stimulated via RAS, RAF and MEKK1/2. More...
TFF_PATHWAY	tff pathway	Trefoil Factors Initiate Mucosal Healing	Maintaining the integrity of the gastrointestinal tract desp...... Maintaining the integrity of the gastrointestinal tract despite the continual presence of microbial flora and injurious agents is essential. Epithelial repair requires restitution and regeneration. During restitution, epithelial cells spread and migrate across the basement membrane to re-establish surface-cell continuity, a process that is independent of cell proliferation. Epithelial continuity depends on a family of small abundant secreted proteins, the trefoil factors (TFFs). The trefoil factor (TFF) family comprises the gastric peptides pS2/TFF1 and spasmolytic peptide (SP)/TFF2, and the intestinal trefoil factor (ITF)/TFF3. Their fundamental action is to promote epithelial-cell restitution within the gastrointestinal tract. TFFs are abundantly secreted onto the mucosal surface by mucus-secreting cells. Their expression is rapidly and coordinately upregulated at the margins of mucosal injury. Secreted TFF acts on adjacent mucosal cell populations either extracellularly (augmenting barrier function) or intracellularly (transcriptional and signalling events). TFF response elements in TFF gene promoters allow increases in TFF expression through auto-induction and cross-induction of other TFFs, in addition to mucin expression and possibly tumor suppression. Cell migration is the result of integrated disruption of cellcell and cellsubstratum adhesion and prevention of apoptosis through cell detachment. Epithelial movement therefore requires integration of motogenic and cell-survival signals. This is achieved by activation of several intracellular signalling pathways that converge on ERK/MAPK and possibly NF-B activation. Serine phosphorylation of the extracellular signal-regulated kinases (ERKs)/mitogen-activated protein kinases (MAPKs) 1 and 2 is central to trefoil factor -mediated signalling, lying downstream of EGFR activation and possibly FAK activation (through recruitment of GRB2 and SOS). Cell migration might result from cooperation between ERK/MAPKs and Rho proteins, FAK activation, beta-integrin clustering and beta-catenin activation. Abrogation of cell death has been shown to require both PI3K activation and ERK/MAPK activation; the former operates through serine/threonine phosphorylation of AKT/protein kinase B, serine phosphorylation of BAD (BCL-2 agonist of cell death) and inhibition of mitochondrial cytochrome c release and formation of the apoptosome (APAF1, caspase-9 (CASP9) and cytochrome c (CYT-c). Translocation of phosphorylated ERK/MAPK to the nucleus leads to amplification and de-restriction of TFF expression to ensure sustained action. More...
SPRY_PATHWAY	spry pathway	Sprouty regulation of tyrosine kinase signals	Four different members of the Sprouty protein family block t...... Four different members of the Sprouty protein family block the cellular proliferation and differentiation induced by several different growth factors, including EGF and FGF. One mechanism by which Sprouty proteins inhibit signaling is through binding to Grb-2, a signaling intermediary between the tyrosine kinase growth factors and the Ras/map kinase pathway. Binding of Sprouty to Grb-2 prevents Grb-2 and Sos-1 from interacting with downstream signaling factors that activate Ras and map kinases, including Ras, Raf-1, Mek1, Erk1/2 and downstream transcription factors. The action of Sprouty as an inhibitor of this pathway requires Sprouty phosphorylation and membrane localization, at the site of the factors it interacts with. The inhibition of growth factor signaling by Sprouty is specific to the Ras pathway since the PI3 Kinase pathway responsible for cell survival signals from growth factor receptors is not inhibited by Sprouty. Tyrosine kinase activity of growth factor receptors is also not affected. The mechanism by which Sprouty inhibits Ras activation may be by blocking the nucleotide exchange activity of Sos. Sprouty expression is induced by growth factor receptor activation of Ras signaling, provided a self-regulatory feedback inhibition mechanism that regulates growth factor signaling through Ras. In addition to blocking the Ras pathway, Sprouty also induces protein tyrosine phosphatase 1B activity. Activation of PTP1B by Sprouty is responsible for the inhibition of cellular migration that Sprouty causes, but is not involved in regulation of cellular proliferation. While blocking receptor tyrosine kinase signaling, at least one member of the Sprouty family, Sprouty-2, also acts by one mechanism to stimulate EGF receptor signaling. Cbl targets the EGF receptor for tagging with ubiquitin and proteolytic destruction. Sprouty-2 binds to Cbl and blocks the ubiquitination and destruction of the EGF receptor, increasing EGF signaling. More...
BARR_MAPK_PATHWAY	barr mapk_pathway	Role of fl-arrestins in the activation and targeting of MAP kinases	The binding of -arrestins to agonist-occupied GPCRs triggers...... The binding of -arrestins to agonist-occupied GPCRs triggers the assembly of a MAP kinase activation complex using -arrestin as a scaffold, with subsequent activation of a -arrestin-bound pool of ERK1/2. The receptor-arrestinERK complexes are localized to endosomal vesicles, and their formation does not result in nuclear translocation of activated ERK1/2 or stimulation of cell proliferation. The function of -arrestin-bound ERK1/2 is presently unknown. Activation of ERK1/2 by -arrestin scaffolds may favor the phosphorylation of plasma membrane, cytosolic, or cytoskeletal ERK1/2 substrates, or it may lead to transcriptional activation through the ERK-dependent activation of other kinases. The model depicts -arrestin scaffolding of the ERK1/2 MAP kinase cascade, based upon data obtained with the protease-activated PAR2 and angiotensin AT1a receptors. A similar mechanism has been proposed for regulation of the JNK3 MAP kinase cascade by AT1a receptors. More...
AT1R_PATHWAY	at1r pathway	Angiotensin II mediated activation of JNK Pathway via Pyk2 dependent signaling	Ang II binding to AT1-R triggers the activation of Ca2+ sign...... Ang II binding to AT1-R triggers the activation of Ca2+ signaling and PKC. The signal is then transmitted to the Pyk2 and further to the small G protein Rac1 but not Cdc42, although the direct activation of Rac1 by Pyk2 is not proved in this study. In turn, Rac1 activates a small G protein-activated kinase whose identity is still controversial, but one of which has been suggested to be PAK1. Finally, the JNK cascade, including MEKK1, SEK1, and JNK, is activated, causing induction of c-Jun gene via binding of ATF2 and c-Jun heterodimer to the junTRE2 site. Ang II is closely involved in the cardiac remodeling by stimulating synthesis of extracellular matrix proteins. It was recently found that expression of fibronectin by Ang II is transcriptionally regulated by AP-1 complex in cardiac fibroblasts. Collagenase gene containg AP-1 sites is also regulated by AP-1 components including c-Jun. AP-1 activity is also enhanced in Ang II-induced cardiac hypertrophy. Expression of ANF is regulated by AP-1 components. More...
CERAMIDE_PATHWAY	ceramide pathway	Ceramide Signaling Pathway	Over 1,000 papers and reviews have been written about the ro...... Over 1,000 papers and reviews have been written about the role of ceramide in the production of programmed cell death or apoptosis. Ceramide is a sphingosine-based lipid-signaling molecule involved in the regulation of cellular differentiation, proliferation, and apoptosis. This diagram represents some of the current understanding of the cascades that couple ceramide to specific signaling pathways. These cascades illustrate that ceramide can be a growth stimulus or proapototic signal. The ultimate ceramide action is determined within the context of other stimuli and by the subcellular topology of its production and is cell-type specific. There are 2 forms of sphingomyelinase, acid (acid-sphingomyelinase:A-SMase) and neutral (neutral-sphingomyelinase N-SMase), that can produce ceramide. TNF-alpha can stimulate either form of sphingomyelinase as can other death receptors. Different domanis of TNF-alpha stimulate the different Smases. N-SMase stimulation is enhanced by the receptor for activated-C kinase 1 (RACK1). The activity of each form is dependent on the local intracellular pH. In the illustration the forms are seperated to reduce confusion however ceramide produced by either method can stimulate either cascade depending on the presence of specific co-factors and activators. A-SMase has been recognized as one of the required molecules to mediate proapoptotic signalling in cell death induced by a diverse array of stresses such as H2O2, Heat, UV exposure and Radiation. ROS generation in mitochondria activates caspase-3 via cooperation of cytochrome c, Aif and caspase-9 and stimulates or increases ceramide generation through A-SMase in a proaptotic activation cycle. Caspase-3 further increases its own activation by proteolytically cleaving ceramide inhibited catalase which is an inhibitor of ROS generation. Ceramide-activated protein kinase(CARK) also known as Kinase Supressor of RAS (KSR) activity is in some cases the switch point in the balance between proapoptotic and antiapoptotic signals and is also cell-type specific. In endothelial cells for example the activation of KSR is required for apoptosis. In contrast in epithelial cells activation of KSR is required for cell proliferation. An additional switch point is the availability of Bad in the cell. Activation of KSR leads to further mitocondrial stimulation or association with RAS and activation of the Raf1 cascade leading to proliferation or differentiation. More...
RACCYCD_PATHWAY	raccycd pathway	Influence of Ras and Rho proteins on G1 to S Transition	The cell cycle transition from G1 to S phase is a key regula...... The cell cycle transition from G1 to S phase is a key regulatory point in the cell cycle. This transition is regulated by the checkpoint kinase cdk2 that activates the G1 to S transition when it is associated with cyclin E. Cdk2/Cyclin E causes the G1 to S transition through phosphorylation of the tumor suppressor Rb, releasing the transcription factor E2F-1. Other pathways acting through Rac, Ras and Rho also regulate the G1 to S transition. Ras regulates cyclin D1 expression to affect the G1 to S transition. Transforming forms of Ras or Raf induce cyclin D1 expression and cause early entry into S phase. Signaling from Ras to Raf to MEK to ERKs induces Cyclin D1 expression, allowing Cyclin D1 to complex with Cdk4 and Cdk6 and phosphorylate Rb. Rac-1 and PAK appear to induce Cyclin D1 expression and induce the G1 to S transition primarily through activation of NF-kB to activate the Cyclin D1 promoter. Rho activates cdk2 and also inhibits p21 and p27 to induce cyclin D1 and stimulate the G1 to S transition. Rho represses p21 expression to block p21 induction by Ras and to allow Ras induced progression from G1 to S. Cells that lack p21 do not require Rho for Ras to induce cell cycle progression from G1 to S phase. The cooperative action of Ras, Rac and Rho to induce Cyclin D1 expression is a key component of oncogenic transformation. More...
FMLP_PATHWAY	fmlp pathway	fMLP induced chemokine gene expression in HMC-1 cells	Neutrophils respond to bacterial infection by releasing reac...... Neutrophils respond to bacterial infection by releasing reactive oxygen species that kill bacteria and by expressing chemokines that attract other immune cells to the site of infection. The multisubunit enzyme NADPH oxidase expressed by neutrophils produces reactive oxygen species rapidly released in what is known as the respiratory burst. Activity of the NADPH oxidase is induced by fMLP receptor ligands, formylated peptides from bacteria. The fMLP receptor is a G-protein coupled receptor, FPR-1, that activates Map kinase pathways and phospholipase C. Phospholipase C activation releases IP3 and calcium, activating protein kinase C and also activating the transcription factor NFAT, which contributes to activation of chemokine genes. One of the components of the NADPH oxidase is p47phox. PKC activation phosphorylates p47phox to activate NADPH oxidase activity. Activation of Map kinase cascades leads to Erk1/Erk2 dependent p47phox phosphorylation as well as activation of the Elk-1 transcription factor and chemokine gene expression. Inhibition of p38 did not affect p47phox phosphorylation, indicating that p38 is not involved in Erk1/2 activation of the NADPH oxidase. Inhibition of p38 did inhibit NADPH oxidase though, indicating that other pathways contribute to activation of this enzyme. The pathways involved in neutrophils activation are important to understand innate immune responses to bacterial infection. More...
MAPK_PATHWAY	mapk pathway	MAPKinase Signaling Pathway	The ever evolving mitogen-activated protein kinase (MAP kina...... The ever evolving mitogen-activated protein kinase (MAP kinase) pathways consist of four major groupings and numerous related proteins which constitute interrelated signal transduction cascades activated by stimuli such as growth factors, stress, cytokines and inflammation. The four major groupings are the Erk (red), JNK or SAPK (blue), p38 (green) and the Big MAPK or ERK5 (light blue) cascades. Signals from cell surface receptors such as GPCRs and growth factor receptors are transduced, directly or via small G proteins such as ras and rac, to multiple tiers of protein kinases that amplify these signals and/or regulate each other. The diagram is organized to illustrate the cascades by the background colors and also the tiers of kinases as indicated down the left hand side and separated by the horizontal dashed lines. In some cascades the first activation tier involves the MAPKKKKs, MAP kinase kinase kinase kinases or MAP4K proteins. The next tier are the serine/threonine MAPKKKs, MAP kinase kinase kinase or MAP3Ks such as RAF, TAK, ASK, and MEKK1. This level has the greatest amount of cross-communication curently known. The serine/threonine/tyrosine MAPKKs, MAP Kinase kinases or MAP2Ks, such as the MKK and MEK kinases, are one step up from the MAP kinase cascade, phosphorylating and activating these kinases. The focal tier, the MAPKs or MAP kinases includes JNK1, p38, and ERKs, and are the kinases that give each cascade its name BR>The endpoints of these cascades, shown in the bottom tier, includes the MAPK activated protein kinases (MAPKAPK) and some of the numerous transcription factors that regulate genes involved in apoptosis, inflammation, cell growth and differentiation NOTES:- The shared color and the bold arrows show the major flow of each cascade. - The smaller arrows indicate cross communication between cascades. In many cases this is restricted to certain cell types or requires additional factors. - Kinases that have been identified as MAP kinases based on sequence or structural homolgies but have not yet been assigned to a cascade have been placed out side the grouping backrgounds. - The PAKs (p21 associated kinases) are not MAPKs but participate in the transduction to the JNK cascade are included for this reason.) - MEK4 appears to function in both the JNK and p38 cascades and so has a mixed color. MEK4 signal is much stronger in the JNK than the p38 cascade and so the bold arrow towards the JNK and the dashed arrow towards the p38 cascade indicate the relative strengths of signaling. - For space and readability concerns not all interactions and stimuli are indicated and the scaffold and phosphatase proteins are not shown. More...
HER2_PATHWAY	her2 pathway	Role of ERBB2 in Signal Transduction and Oncology	Her2 or ERBB2 belongs to a class of proteins having high hom...... Her2 or ERBB2 belongs to a class of proteins having high homology with epidermal growth factor receptor (EGFR or ERBB1). It encodes a protein with the molecular weight of 185 KDa. Unlike other members of EGFR family, no ligand for Her2 has been found and it usually associates with members of ERBB1 family to form functional heterodimers. It has been shown that it can form dimers with ERBB (EGFR), ERBB3 and ERBB4 as well as gp130 subunits of IL-6 receptor. In at least some cell types, the association between gp130 and HRBB2 is essential for HRBB2-ERBB3 phosphorylation and subsequent MAP kinase signaling. Although ERBB1 can form homodimers, the signaling for ERBB1 is usually transient and the receptor undergoes internalization after ligand binding and activation. EGFR-HER2 complex increases the signaling capacity of EGFR by increasing the ligand affinity as well as the recycling of the heterodimer. Of all the ERBB heterodimers, ERBB2-ERBB3 heterodimers perhaps elicit the strongest signal. Removing ERBB3 from the cell has a drastic effect on ERBB2 mediated signaling and downstream effectors. The clinical importance of HER2 cannot be overstated. In addition, monoclonal antibody (Herceptin) against this receptor has been shown to be an effective treatment of breast cancer patients who have a high level of HER2 over expression. More...
ERK5_PATHWAY	erk5 pathway	Role of Erk5 in Neuronal Survival	Axons extend significant distances to innervate target tissu...... Axons extend significant distances to innervate target tissues. At the site of innervation, target tissues release neurotrophins including NGF, BDNF and neurotrophin-3 that stimulate the survival of the associated neuron. Local signaling by activated Trk receptors at the synaptic terminus mediates some presynaptic neuronal responses to neurotrophins. Map kinase pathways activated by Trk receptor activate Erk1 and Erk2 at the terminus stimulating axonal growth, and PI3K activates AKT in the terminus as well. Activation of these kinases does not propagate a signal to the cell body though and does not induce a transcriptional response. This local signaling at the terminus or local signaling at the cell body appears distinct from the signaling pathway that transduces the survival signal from the target tissue. Retrograde axonal transport plays an essential role in neuronal survival induced by neurotrophins released at the target tissue. Failure of retrograde neurotrophin signaling may play a role in neurodegenerative conditions. The neuronal survival signal is initiated by binding of neurotrophins to Trk receptors in the presynaptic membrane, then travels back along the axon to the neuronal cell body. To transmit the signal back along the axon, activated Trk receptors are internalized through receptor-mediated endocytosis and receptor containing vesicles then rapidly travel back to the cell body along axonal microtubules. Several reports indicate that neurotrophins remain receptor-bound during the retrograde axonal transport to the cell body, but recently it was reported that retrograde transport of NGF was not required to induce neuronal survival. Once in the cell body, Trk receptors activate multiple pathways. A key pathway activated by Trk after retrograde transport involves Erk5, also called BMK1. Trk activates Mek5, which activates Erk5, inducing phosphorylation of the CREB and Mef2 transcription factors. Erk5 does not directly phosphorylate CREB, but translocates into the nucleus and phosphorylates the kinase Rsk, which phosphorylates CREB in turn. Both CREB and Mef2 induce a transcriptional program that contributes to neuronal survival. Local activation of Erk5 on the cell body does not appear to induce the same signaling system or neuronal survival, indicating that the retrograde transport is an essential part of the survival signaling system. Also, activation of Erk1 and Erk2 in the cell body can induce CREB activation and neuronal survival, but these kinases are not activated by neurotrophins applied to the axonal terminus. Another pathway activated by retrograde neurotrophin signaling though Erk5 is PI3 Kinase. More...
CDMAC_PATHWAY	cdmac pathway	Cadmium induces DNA synthesis and proliferation in macrophages	Exposure to divalent cadmium ions (Cd2+) is a known cancer r...... Exposure to divalent cadmium ions (Cd2+) is a known cancer risk factor, but the molecular mechanisms responsible for the inappropriate induction of cellular proliferation by cadmium are still being figured out. One cellular model used to study this process is macrophages grown in culture. In cultured macrophages, cadmium acts both at the cell surface and in the cytoplasm to induce proliferation. At the cell surface, cadmium interacts with a pertussis-sensitive cell surface receptor, probably a Gi-coupled GPCR, to stimulate proliferation. Cadmium can enter cells through calcium ion channels and once in cells affects calcium release by the ER. In addition to changes in intracellular calcium, the proliferative effects of cadmium are mediated by the Ras/Map kinase pathway, and also NF-kB. Inhibition of phospholipase C, map kinases, or NF-kB with a variety of pharmacological inhibitors all blocked the activation of cellular proliferation by cadmium. Protein kinase C is also activated by cadmium, upstream of the Map kinase pathway. Changes in transcription induced by cadmium include induction of immediate early genes like fos, jun, and myc. In addition to inducing cellular proliferation, cadmium also is slightly genotoxic due to inhibition of DNA repair, activates stress genes, and inhibits the immune system. The immuno-modulatory effects observed with cadmium treatment may also involvement transcriptional disregulation, including the expression of cytokines such as IL-4, IL-10, and TNF-alpha. Although macrophages have been used for many studies, other cell types are also the target of cadmiums toxicity. More...

MAPK1 related Reactome pathways (count: 32)

ID	Name	Description
Gene mapped Reactome pathways
REACT_12077	signalling to_p38_via_rit_and_rin	RIT and RIN are two small guanine nucleotide binding protein...... RIT and RIN are two small guanine nucleotide binding proteins that share more than 50% sequence identity with RAS, including highly conserved core effector domains. Unlike RAS, the C termini of RIT and RIN lack a typical prenylation motif (CAAX, XXCC, or CXC) required for the association of RAS proteins with the plasma membrane. RIT is expressed in all tissues, whereas RIN is neuron-specific. They have similar signalling properties and are activated by NGF through unknown exchange factors. They signal to ERKs and p38 MAP kinase. They mainly lead to p38 activation via the BRAF-MEK kinase cascade. More...
REACT_15370	neuroransmitter receptor_binding_and_downstream_transmission_in_the_postsynaptic_cell	The neurotransmitter in the synaptic cleft released by the p...... The neurotransmitter in the synaptic cleft released by the pre-synaptic neuron binds specific receptors located on the post-synaptic terminal. These receptors are either ion channels or G protein coupled receptors that function to transmit the signals from the post-synaptic membrane to the cell body. More...
REACT_12433	nuclear events_kinase_and_transcription_factor_activation	An important function of the kinase cascade triggered by neu...... An important function of the kinase cascade triggered by neurotrophins is to induce the phosphorylation and activation of transcription factors in the nucleus to initiate new programs of gene expression. Transcription factors directly activated by neurotrophin signalling are responsible for induction of immediate-early genes, many of which are transcription factors. These in turn are involved in the induction of delayed-early genes. More...
REACT_12436	erks are_inactivated	MAP Kinases are inactivated by a family of protein named MAP...... MAP Kinases are inactivated by a family of protein named MAP Kinase Phosphatases (MKPs). They act through dephosphorylation of threonine and/or tyrosine residues within the signature sequence -pTXpY- located in the activation loop of MAP kinases (pT=phosphothreonine and pY=phosphotyrosine). MKPs are divided into three major categories depending on their preference for dephosphorylating; tyrosine, serine/threonine and both the tyrosine and threonine (dual specificity phoshatases or DUSPs). The tyrosine-specific MKPs include PTP-SL, STEP and HePTP, serine/threonine-specific MKPs are PP2A and PP2C, and many DUSPs acting on MAPKs are known. Activated MAP kinases trigger activation of transcription of MKP genes. Therefore, MKPs provide a negative feedback regulatory mechanism on MAPK signaling, by inactivating MAPKs via dephosphorylation, in the cytoplasm and the nucleus. Some MKPs are more specific for ERKs, others for JNK or p38MAPK. More...
REACT_12056	trka signalling_from_the_plasma_membrane	Trk receptors signal from the plasma membrane and from intra...... Trk receptors signal from the plasma membrane and from intracellular membranes, particularly from early endosomes. Signalling from the plasma membrane is fast but transient; signalling from endosomes is slower but long lasting. Signalling from the plasma membrane is annotated here. TRK signalling leads to proliferation in some cell types and neuronal differentiation in others. Proliferation is the likely outcome of short term signalling, as observed following stimulation of EGFR (EGF receptor). Long term signalling via TRK receptors, instead, was clearly shown to be required for neuronal differentiation in response to neurotrophins. More...
REACT_9417	signaling by_egfr	The epidermal growth factor receptor (EGFR) is one member of...... The epidermal growth factor receptor (EGFR) is one member of the ErbB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands leads to autophosphorylation of tyrosine residues on the receptor and subsequent activation of signal transduction pathways that are involved in regulating cellular proliferation, differentiation, and survival. Ligand binding with EGFR results in receptor homo- or heterodimerization at the cell surface. Trans-autophosphorylation of the EGFR tyrosine kinase domains occurs and the phosphorylated tyrosine kinase residues serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, such as Ras, which then stimulate an intracellular signal transduction cascade. More...
REACT_21308	map kinases_activation_in_tlr_cascade	Mitogen activated protein kinase. There are three major grou...... Mitogen activated protein kinase. There are three major groups of MAP kinases the extracellular signal-regulated protein kinases ERK1/2. the p38 MAP kinase. the c-Jun NH-terminal kinases JNK. ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr). MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK. The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites. The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear. More...
REACT_6783	toll like_receptor_3_cascade	Toll-like receptor 3 (TLR3) as was shown for mammals is expr...... Toll-like receptor 3 (TLR3) as was shown for mammals is expressed on myeloid dendritic cells, respiratory epithelium, macrophages, and appears to play a central role in mediating the antiviral and inflammatory responses of the innate immunity in combating viral infections. Mammalian TLR3 recognizes dsRNA, and that triggers the receptor to induce the activation of NF-kappaB and the production of type I interferons (IFNs). dsRNA-stimulated phosphorylation of two specific TLR3 tyrosine residues (Tyr759 and Tyr858) is essential for initiating TLR3 signaling pathways. More...
REACT_12058	signalling to_erks	Neurotrophins utilize multiple pathways to activate ERKs (ER...... Neurotrophins utilize multiple pathways to activate ERKs (ERK1 and ERK2), a subgroup of the large MAP kinase (MAPK) family, from the plasma membrane. The major signalling pathways to ERKs are via RAS, ocurring from caveolae in the plasma membrane or from clathrin-coated vesicles, and via RAP1, taking place in early endosomes. Whereas RAS activation by NGF is transient, RAP1 activation by NGF is sustained for hours. More...
REACT_6900	signaling in_immune_system	Humans are exposed to millions of potential pathogens daily,...... Humans are exposed to millions of potential pathogens daily, through contact, ingestion, and inhalation. Our ability to avoid infection depends on the adaptive immune system and during the first critical hours and days of exposure to a new pathogen, our innate immune system. More...
REACT_20568	creb phophorylation_through_the_activation_of_ras	Ca2+ influx through the NMDA receptor initiates subsequent m...... Ca2+ influx through the NMDA receptor initiates subsequent molecular pathways that have a defined role in establishing long-lasting synaptic changes. The molecular signaling initiated by a rise in Ca2+ within the spine leads to phosphorylation of Cyclic AMP Response Element binding protein (CREB) at serine 133 which is involved in the transcription of genes that results in long lasting changes in the synapse. The phosphorylation of CREB by increased Ca2+ can be brought about by distinct molecular pathways that may involve MAP kinase, activation of adenylate cyclase, activation of CaMKII and/or the activation of CaMKIV. More...
REACT_18266	axon guidance	Axon guidance / axon pathfinding is the process by which neu...... Axon guidance / axon pathfinding is the process by which neurons send out axons to reach the correct targets. Growing axons have a highly motile structure at the growing tip called the growth cone, which senses the guidance cues in the environment through guidance cue receptors and responds by undergoing cytoskeletal changes that determine the direction of axon growth. Guidance cues present in the surrounding environment provide the necessary directional information for the trip. These extrinsic cues have been divided into attractive or repulsive signals that tell the growth cone where and where not to grow. Genetic and biochemical studies have led to the identification of highly conserved families of guidance molecules and their receptors that guide axons. These include netrins, Slits, semaphorins, and ephrins, and their cognate receptors, DCC and or uncoordinated-5 (UNC5), roundabouts (Robo), neuropilin and Eph. In addition, many other classes of adhesion molecules are also used by growth cones to navigate properly which include NCAM and L1CAM. More...
REACT_18334	ncam signaling_for_neurite_out_growth	The neural cell adhesion molecule, NCAM, is a member of the ...... The neural cell adhesion molecule, NCAM, is a member of the immunoglobulin (Ig) superfamily and is involved in a variety of cellular processes of importance for the formation and maintenance of the nervous system. The role of NCAM in neural differentiation and synaptic plasticity is presumed to depend on the modulation of intracellular signal transduction cascades. NCAM based signaling complexes can initiate downstream intracellular signals by at least two mechanisms: (1) activation of FGFR and (2) formation of intracellular signaling complexes by direct interaction with cytoplasmic interaction partners such as Fyn and FAK. Tyrosine kinases Fyn and FAK interact with NCAM and undergo phosphorylation and this transiently activates the MAPK, ERK 1 and 2, cAMP response element binding protein (CREB) and transcription factors ELK and NFkB. CREB activates transcription of genes which are important for axonal growth, survival, and synaptic plasticity in neurons. NCAM1 mediated intracellular signal transduction is represented in the figure below. The Ig domains in NCAM1 are represented in orange ovals and Fn domains in green squares. The tyrosine residues susceptible to phosphorylation are represented in red circles and their positions are numbered. Phosphorylation is represented by red arrows and dephosphorylation by yellow. Ig, Immunoglobulin domain; Fn, Fibronectin domain; Fyn, Proto-oncogene tyrosine-protein kinase Fyn; FAK, focal adhesion kinase; RPTPalpha, Receptor-type tyrosine-protein phosphatase; Grb2, Growth factor receptor-bound protein 2; SOS, Son of sevenless homolog; Raf, RAF proto-oncogene serine/threonine-protein kinase; MEK, MAPK and ERK kinase; ERK, Extracellular signal-regulated kinase; MSK1, Mitogen and stress activated protein kinase 1; CREB, Cyclic AMP-responsive element-binding protein; CRE, cAMP response elements. More...
REACT_762	irs related_events	IRS is one of the mediators of insulin signalling events. It...... IRS is one of the mediators of insulin signalling events. It is activated by phosphorylation and triggers a cascade of events involving PI3K, SOS, RAF and the MAP kinases. The proteins mentioned under IRS are examples of IRS family members acting as indicated. More family members are to be confirmed and added in the future. More...
REACT_16888	signaling by_pdgf	Platelet-derived Growth Factor (PDGF) is a potent stimulator...... Platelet-derived Growth Factor (PDGF) is a potent stimulator of growth and motility of connective tissue cells such as fibroblasts and smooth muscle cells as well as other cells such as capillary endothelial cells and neurons.The PDGF family of growth factors is composed of four different polypeptide chains encoded by four different genes. The classical PDGF chains, PDGF-A and PDGF-B, and more recently discovered PDGF-C and PDGF-D. The four PDGF chains assemble into disulphide-bonded dimers via homo- or heterodimerization, and five different dimeric isoforms have been described so far; PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. It is notable that no heterodimers involving PDGF-C and PDGF-D chains have been described. PDGF exerts its effects by binding to, and activating, two protein tyrosine kinase (PTK) receptors, alpha and beta. These receptors dimerize and undergo autophosphorylation. The phosphorylation sites then attract downstream effectors to transduct the signal into the cell. More...
REACT_12076	frs2 mediated_activation	The adaptor protein Frs2 (Fibroblast growth factor receptor ...... The adaptor protein Frs2 (Fibroblast growth factor receptor substrate 2) can mediate the prolonged activation of the MAPK (ERK) cascade. More...
REACT_12599	erk mapk_targets	ERK/MAPK kinases have a number of targets within the nucleus...... ERK/MAPK kinases have a number of targets within the nucleus, usually transcription factors or other kinases. The best known targets, ELK1, ETS1, ATF2, MITF, MAPKAPK2, MSK1, RSK1/2/3 and MEF2 are annotated here. More...
REACT_999	shc related_events	SHC is one of the mediators of insulin signalling events. It...... SHC is one of the mediators of insulin signalling events. It is activated by phosphorylation and triggers a cascade of events involving SOS, RAF and the MAP kinases. More...
REACT_20593	post nmda_receptor_activation_events	Ca2+ influx through the NMDA receptor initiates subsequent m...... Ca2+ influx through the NMDA receptor initiates subsequent molecular pathways that have a defined role in establishing long-lasting synaptic changes. The molecular signaling initiated by a rise in Ca2+ within the spine leads to phosphorylation of Cyclic AMP Response Element binding protein (CREB) at serine 133 which is involved in the transcription of genes that results in long lasting changes in the synapse. The phosphorylation of CREB by increased Ca2+ can be brought about by distinct molecular pathways that may involve MAP kinase, activation of adenylate cyclase, activation of CaMKII and/or the activation of CaMKIV. More...
REACT_661	shc mediated_signalling	Release of phospho-SHC from the insulin receptor triggers a ...... Release of phospho-SHC from the insulin receptor triggers a cascade of signalling events via SOS, RAF and the MAP kinases. More...
REACT_11061	signalling by_ngf	Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles i...... Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. They signal through two types of receptors: TRK tyrosine kinase receptors (TRKA, TRKB, TRKC), which specifically interact with the different neurotrophins, and p75NTR, which interacts with all neurotrophins. TRK receptors are reported in a variety of tissues in addition to neurons. p75NTRs are also widespread. Neurotrophins and their receptors are synthesized as several different splice variants, which differ in terms of their biological activities. The nerve growth factor (NGF) was the first growth factor to be identified and has served as a model for studying the mechanisms of action of neurotrophins and growth factors. The mechanisms by which NGF generates diverse cellular responses have been studied extensively in the rat pheochromocytoma cell line PC12. When exposed to NGF, PC12 cells exit the cell cycle and differentiate into sympathetic neuron-like cells. Current data show that signalling by the other neurotrophins is similar to NGF signalling. More...
REACT_21328	mapk targets_nuclear_events_mediated_by_map_kinases	MAPKs are protein kinases that, once activated, phosphorylat...... MAPKs are protein kinases that, once activated, phosphorylate their specific cytosolic or nuclear substrates at serine and/or threonine residues. Such phosphorylation events can either positively or negatively regulate substrate, and thus entire signaling cascade activity. The major cytosolic target of activated ERKs are RSKs. Other ERK nuclear targets include c-Myc, HSF1 (Heat-Shock Factor-1), STAT1/3 (Signal Transducer and Activator of Transcription-1/3), and many more transcription factors. Activated p38 MAPK is able to phosphorylate a variety of substrates, including transcription factors STAT1, p53, ATF2 (Activating transcription factor 2), MEF2 (Myocyte enhancer factor-2), protein kinases MSK1, MNK, MAPKAPK2/3, death/survival molecules (Bcl2, caspases), and cell cycle control factors (cyclin D1). JNK, once activated, phosphorylates a range of nuclear substrates, including transcription factors Jun, ATF, Elk1, p53, STAT1/3 and many other factors. JNK has also been shown to directly phosphorylate many nuclear hormone receptors. For example, peroxisome proliferator-activated receptor 1 (PPAR-1) and retinoic acid receptors RXR and RAR are substrates for JNK. Other JNK targets are heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Other adaptor and scaffold proteins have also been characterized as nonnuclear substrates of JNK. More...
REACT_12033	signalling to_ras	Signalling through Shc adaptor proteins appears to be identi...... Signalling through Shc adaptor proteins appears to be identical for both NGF and EGF. It leads to a fast, but transient, MAPK/ERK activation, which is insufficient to explain the prolonged activation of MAPK found in NGF-treated cells. More...
REACT_17025	down stream_signal_transduction	The role of autophosphorylation sites on PDGF receptors are ...... The role of autophosphorylation sites on PDGF receptors are to provide docking sites for downstream signal transduction molecules which contain SH2 domains. The SH2 domain is a conserved motif of around 100 amino acids that can bind a phosphorylated tyrosine residue. These downstream molecules are activated upon binding to, or phosphorylated by, the receptor kinases intrinsic to PDGF receptors. Some of the dowstream molecules are themselves enzymes, such as phosphatidylinositol 3'-kinase (PI3K), phospholipase C (PLC-gamma), the Src family of tyrosine kinases, the tyrosine phosphatase SHP2, and a GTPase activating protein (GAP) for Ras. Others such as Grb2 are adaptor molecules which link the receptor with downstream catalytic molecules. More...
REACT_12606	grb2 events_in_egfr_signaling	Autophosphorylation of tyrosine residues are docking sites f...... Autophosphorylation of tyrosine residues are docking sites for many downstream effectors in EGFR signaling. SH2-containing phosphotyrosine-binding domains of adaptor proteins like GRB2 is one such example. GRB2 is constitutively associated with SOS, a guanine nucleotide exchange factor of Ras. GRB2 binding to phosphorylated EGFR results in the recruitment of SOS to the plasma membrane where it comes in proximity to Ras. This mechanism has been seen to be the model for Ras activation. More...
REACT_524	sos mediated_signalling	SOS is recruited to the plasma membrane and mediates activat...... SOS is recruited to the plasma membrane and mediates activation of Ras. More...
REACT_6966	toll receptor_cascades	In human, ten members of the Toll-like receptor (TLR) family...... In human, ten members of the Toll-like receptor (TLR) family (TLR1-TLR10) have been identified (TLR11 has been found in mouse, but not in human). All TLRs have a similar Toll/IL-1 receptor (TIR) domain in their cytoplasmic region and an Ig-like domain in the extracellular region, where each is enriched with a varying number of leucine-rich repeats (LRRs). Each TLR can recognize specific microbial pathogen components. The binding pathogens component of the TLRs initializes signaling pathways that lead to induction of Interferon alpha/beta. There are three main signaling pathways: the first is a MyD88-dependent pathway that is common to all TLRs, except TLR3; the second is a TRAM-dependent pathway that is peculiar to TLR3 and TLR4 and is mediated by TRIF and RIP1; and the third is a TRAF6-mediated pathway peculiar to TLR3. More...
REACT_13477	transmission across_chemical_synapses	Chemical synapses are specialized junctions that are used fo...... Chemical synapses are specialized junctions that are used for communication between neurons, neurons and muscle or gland cells. The synapse involves a pre-synaptic neuron and a post-synaptic neuron, muscle cell or glad cell. The pre and the post-synaptic cell are separated by a gap of 20nm called the synaptic cleft. The signals pass in a unidirection from pre-synaptic to post-synaptic. The pre-synaptic neuron communicates via the release of neurotransmitter which bind the receptors on the post-synaptic cell. More...
REACT_6782	traf6 mediated_induction_of_the_antiviral_cytokine_ifn_alpha_beta_cascade	In human, together with ubiquitin-conjugating E2-type enzyme...... In human, together with ubiquitin-conjugating E2-type enzymes UBC13 and UEV1A and IKK(NEMO), leading to the activation of the kinases. Xia et all., 2009 demonstrated in vitro that unlike polyubiquitin chains covalently attached to TRAF6 or IRAK, TAB2 and NEMO-associated ubiquitin chains were found to be unanchored and susceptible to N-terminal ubiquitin cleavage. Only K63-linked polyubiquitin chains, but not monomeric ubiquitin, activated TAK1 in a dose-dependent manner.Optimal activation of the IKK complex was achieved using ubiquitin polymers containing both K48 and K63 linkages. Furthermore, the authors proposed that the TAK1 complexes might be brougt in close proximity by binding several TAB2/3 to a single polyubiquitin chain to facilitate TAK1 kinases trans-phosphorylation. Alternativly, the possibility that polyUb binding promotes allosteric activation of TAK1 complex should be considered. More...
REACT_21326	activation of_the_ap1_family_of_transcription_factors	Activator protein-1 (AP-1) is a collective term referring to...... Activator protein-1 (AP-1) is a collective term referring to a group of transcription factors that bind to promoters of target genes in a sequence-specific manner. AP-1 family consists of hetero- and homodimers of bZIP (basic region leucine zipper) proteins, mainly of Jun-Jun, Jun-Fos or Jun-ATF. AP-1 members are involved in the regulation of a number of cellular processes including cell growth, proliferation, survival, apoptosis, differentiation, cell migration. The ability of a single transcription factor to determine a cell fate critically depends on the relative abundance of AP-1 subunits, the composition of AP-1 dimers, the quality of stimulus, the cell type, the co-factor assembly. AP-1 activity is regulated on multiple levels; transcriptional, translational and post-translational control mechanisms contribute to the balanced production of AP-1 proteins and their functions. Briefly, regulation occurs through: effects on jun, fos, atf gene transcription and mRNA turnover. AP-1 protein members turnover. post-translational modifications of AP-1 proteins that modulate their transactivation potential (effect of protein kinases or phosphatases). interactions with other transcription factors that can either induce or interfere with AP-1 activity. More...
REACT_20563	activation of_nmda_receptor_upon_glutamate_binding_and_postsynaptic_events	NMDA receptors are a subtype of ionotropic glutamate recepto...... NMDA receptors are a subtype of ionotropic glutamate receptors that are specifically activated by a glutamate agonist N-methyl-D-aspartate (NMDA). Activation of NMDA receptor involves opening of the ion channel that allows the influx of Ca2+. NMDA receptors are central to activity dependent changes in synaptic strength and are predominantly involved in the synaptic plasticity that pertain to learning and memory. A unique feature of NMDA receptor unlike other glutamate receptors is the requirement of dual activation of the NMDA receptor, which require both voltage dependent and ligand dependent activation. At resting membrane potential the NMDA receptors are blocked by Mg2+. The voltage dependent Mg2+ block is relieved upon depolarization of the post-synpatic membrane. The ligand dependent activation of the NMDA receptor requires co-activation by two ligands, namely glutamate and glycine. NMDA receptors are coincidence detector, and are activated only if there is simultaneous activation of both pre and post-synaptic cell. Upon activation NMDA receptors allow the influx of Ca2+ that initiates various molecular signaling cascades that are involved in the process of learning and memory. More...
REACT_6802	innate immunity_signaling	Innate immunity encompases the nonspecific part of immunity ...... Innate immunity encompases the nonspecific part of immunity tha are part of an individual's natural biologic makeup More...

MAPK1 related interactors from protein-protein interaction data in HPRD (count: 161)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
MAPK1	TNFRSF25	Yes	in vitro;in vivo	11606045
MAPK1	IER3	No	in vitro;in vivo	12356731
MAPK1	CEBPB	No	in vitro	8384717
MAPK1	KLF11	No	in vitro;in vivo	12006497
MAPK1	CDX2	No	in vitro	16027724
MAPK1	PTPN7	No	in vitro;in vivo	10702794 , 10206983 , 12592337
MAPK1	ZFP36	No	in vitro;in vivo	7768935 , 95286626
MAPK1	GAB1	No	in vitro	15379552
MAPK1	RGS19	No	in vitro;in vivo	10993892
MAPK1	PRKCZ	No	in vivo	15721486
MAPK1	EPOR	No	in vivo	12538595
MAPK1	SCNN1G	No	in vitro	11805112
MAPK1	BCL2	No	in vivo	15225643 , 10567572 , 12039864
MAPK1	LIPE	Yes	in vitro	11581251
MAPK1	GABRR1	Yes	in vitro	12175859
MAPK1	CEP55	No	in vitro	16198290
MAPK1	PLCB1	No	in vitro	11481231
MAPK1	SHC1	No	in vitro;in vivo	10996427
MAPK1	IQGAP1	No	in vitro;in vivo	1497021909368021
MAPK1	RPS6KA1	No	in vitro;in vivo	12594221 , 9915826 , 12832467 , 9430688 , 12618428
MAPK1	GRB2	No	in vivo	8994038
MAPK1	NCOA1	No	in vitro;in vivo	10660621
MAPK1	DUSP16	No	in vivo	11489891 , 12794087
MAPK1	CD19	No	in vitro	10706702
MAPK1	NR3C1	Yes	in vitro;in vivo	12351702 , 9199329
MAPK1	PEA15	No	in vitro;in vivo;yeast 2-hybrid	11702783
MAPK1	SH2D3C	No	in vivo	10692442
MAPK1	SORBS3	No	in vivo	15184391
MAPK1	FCGR2B	No	in vivo	15081531
MAPK1	RPS6KA2	No	in vitro;in vivo	8939914 , 9915826
MAPK1	NDE1	No	in vitro	12556484
MAPK1	PPARG	No	in vitro;in vivo	9030579
MAPK1	TP53	No	in vitro;in vivo	11409876 , 15116093 , 12091386
MAPK1	MAPKAPK5	No	in vitro;in vivo	9628874
MAPK1	METAP2	No	in vitro	15544353
MAPK1	STAT5A	No	in vitro;in vivo	10194762 , 10996427
MAPK1	UBTF	No	in vitro;in vivo	11741541
MAPK1	PTPN5	No	in vitro;in vivo	9857190
MAPK1	GRB10	No	in vitro;in vivo	15952796
MAPK1	RXRA	No	in vitro;in vivo	12048211
MAPK1	CSDA	No	in vitro	16198352
MAPK1	DUSP4	Yes	in vivo	7535768
MAPK1	DUSP5	No	in vitro;in vivo;yeast 2-hybrid	15713638
MAPK1	RAF1	No	in vitro;in vivo	15664191
MAPK1	MYB	No	in vitro;in vivo	8960373
MAPK1	SP1	No	in vitro;in vivo	11904305
MAPK1	RB1	No	in vitro	15489336
MAPK1	KHDRBS1	No	in vitro	12478298
MAPK1	HSF4	No	in vivo	16581800
MAPK1	RET	No	in vitro	16153436
MAPK1	STAT5B	No	in vitro	10996427
MAPK1	TSC2	No	in vitro;in vivo	15851026 , 15342917
MAPK1	MBP	Yes	in vitro	9792705 , 12760422 , 15380617
MAPK1	DUSP3	No	in vitro;in vivo	10224087 , 12840032
MAPK1	ARRB2	No	in vitro	11226259
MAPK1	RPS6KA3	No	in vivo	12832467 , 9915826
MAPK1	RPS6KB1	No	in vitro;in vivo	12054624 , 11279232
MAPK1	MITF	No	in vitro;in vivo	9440696
MAPK1	ARRB1	No	in vitro	10347142 , 9388255
MAPK1	PTPN1	Yes	in vitro	12082107
MAPK1	DAPK1	No	in vitro;yeast 2-hybrid	15616583
MAPK1	SMAD4	No	in vitro;in vivo	12801888
MAPK1	GAB2	No	in vitro;in vivo	15356145
MAPK1	SOS1	No	in vitro;in vivo	8816480
MAPK1	PXN	No	in vitro	14636584
MAPK1	PAK1	No	in vitro;in vivo	15542607
MAPK1	PPP1CA	No	in vitro	12624094
MAPK1	LIFR	No	in vivo	7777512
MAPK1	STAT3	No	in vitro;in vivo	11350938 , 10521505 , 9343414 , 10446219 , 12576423 , 14551213 , 9872331 , 12763138
MAPK1	GORASP2	No	in vitro	11408587
MAPK1	TNFSF11	No	in vitro;in vivo	10635328
MAPK1	PPP1R9B	No	in vitro;in vivo	15728359
MAPK1	PAK2	No	in vitro	15031289
MAPK1	ERF	No	in vitro;in vivo	10330152
MAPK1	SMAD3	No	in vitro;in vivo	16156666 , 10197981
MAPK1	TH	No	in vivo	14570886
MAPK1	SREBF1	No	in vitro	10915800
MAPK1	EGFR	No	in vitro;in vivo	12556561
MAPK1	FRS3	No	in vitro;in vivo;yeast 2-hybrid	15485655
MAPK1	ELK1	No	in vitro	8586671 , 8208531 , 8386592 , 16291755
MAPK1	CALCOCO1	No	in vitro	15489336
MAPK1	GATA1	Yes	in vitro	15967790
MAPK1	TCF3	No	in vivo	14592976
MAPK1	JUND	No	in vitro;in vivo	14676207
MAPK1	EIF4EBP1	No	in vitro;in vivo	9405468 , 8083223 , 9092573 , 10942774 , 12105188
MAPK1	KRT8	No	in vitro;in vivo	11788583 , 11781324 , 9211903
MAPK1	DUSP6	No	in vitro;in vivo	15632084
MAPK1	BCL6	Yes	in vitro	9649500
MAPK1	MKNK1	No	in vitro;yeast 2-hybrid	9155017
MAPK1	VAV1	No	in vivo	9013873 , 8900182
MAPK1	PLAT	No	in vitro	15861134
MAPK1	CAV1	No	in vivo	12388423
MAPK1	MCL1	No	in vitro	15241487
MAPK1	RPS6KA4	No	in vitro;in vivo	9687510
MAPK1	MAFA	No	in vitro;in vivo	11416124
MAPK1	FRS2	No	in vitro	12419216
MAPK1	PPARA	No	in vitro	10187842
MAPK1	SREBF2	No	in vitro	10627507
MAPK1	UBR5	No	in vitro;in vivo	12594221
MAPK1	NCOA3	No	in vitro	10866661
MAPK1	PTPRH	No	in vivo	11278335
MAPK1	MAPKSP1	No	in vitro	11266467
MAPK1	IRS1	No	in vitro	16131083
MAPK1	PRKCD	No	in vivo	12759139
MAPK1	TNFRSF1A	Yes	in vitro	11606045
MAPK1	TGIF1	No	in vitro;in vivo	11226163
MAPK1	GATA2	No	in vitro	7876160
MAPK1	CASP9	No	in vitro;in vivo	12792650
MAPK1	PRKCE	No	in vivo	11350735
MAPK1	TNIP1	No	in vitro;in vivo;yeast 2-hybrid	12220502
MAPK1	PTPRE	No	in vitro	12754301
MAPK1	CMTM3	No	in vivo	15087455
MAPK1	IFNAR1	No	in vitro;in vivo	9029147
MAPK1	PPP2CA	No	in vitro	12624094
MAPK1	BRAF	No	in vitro	14654779
MAPK1	C1QBP	No	in vitro;in vivo	11866440
MAPK1	LCK	No	in vitro;in vivo	8626561 , 8506364 , 8618896
MAPK1	CASP8	No	in vivo	17290218
MAPK1	NGFR	Yes	in vitro;in vivo	8407983
MAPK1	TPR	Yes	in vitro;in vivo	12594221
MAPK1	MAP3K1	No	in vivo	10969079
MAPK1	SNCA	No	in vivo	11279280
MAPK1	NTRK3	Yes	in vitro;in vivo	11205744 , 9973222
MAPK1	GJA1	No	in vitro;in vivo	12637502 , 8631994 , 9535909 , 9535905
MAPK1	SMAD1	No	in vitro;in vivo	9335504
MAPK1	FOS	Yes	in vitro;in vivo	7816602 , 8248197 , 12972619
MAPK1	PTPRR	No	in vitro;in vivo;yeast 2-hybrid	9857190 , 10419510 , 16148006
MAPK1	NR4A1	No	in vitro;in vivo	11883936
MAPK1	LRPAP1	No	in vitro	15342917
MAPK1	MKNK2	No	in vitro;yeast 2-hybrid	9155017 , 11013076
MAPK1	FHL3	No	in vitro	14729955
MAPK1	PLK3	No	in vitro	15021912
MAPK1	SLC9A1	No	in vitro	15253667
MAPK1	MAP2K1	No	in vitro;in vivo;yeast 2-hybrid	11823456 , 11352917 , 11741894 , 8157000 , 12594221 , 11134045
MAPK1	PEBP1	No	in vitro;in vivo	10757792 , 10490027
MAPK1	DUSP2	No	in vitro	16288922
MAPK1	DUSP9	No	yeast 2-hybrid	11988087
MAPK1	DYRK1B	No	in vitro	10910078
MAPK1	AR	Yes	in vitro;in vivo	9725910 , 10318905
MAPK1	CAD	Yes	in vitro	12438317
MAPK1	KSR2	No	in vitro	12975377
MAPK1	YBX1	Yes	in vitro	16198352
MAPK1	MAPK1	Yes	in vitro	9857190 , 9535927 , 1712480 , 1378617 , 91184134 , 9604935
MAPK1	HDAC4	No	in vitro	11114188
MAPK1	ESR1	Yes	in vitro;in vivo	12093745 , 9528769
MAPK1	ETS1	No	in vitro	16045329
MAPK1	HSP90AA1	No	in vivo	11748628
MAPK1	NKX2-1	No	in vitro;in vivo	10733581
MAPK1	NEK2	No	in vitro;in vivo;yeast 2-hybrid	15358203
MAPK1	GMFB	No	in vivo	8639570
MAPK1	DUSP7	No	in vivo	9788880
MAPK1	NR5A1	No	in vivo	10230405
MAPK1	NEFH	No	in vitro;in vivo	9592082
MAPK1	TOB1	Yes	in vitro;in vivo;yeast 2-hybrid	12151396 , 12050114
MAPK1	MAPK8	Yes	in vivo	15778365
MAPK1	SNCG	No	in vivo	12121974
MAPK1	DUSP1	No	in vitro;in vivo;yeast 2-hybrid	11278799 , 10617468 , 16286470 , 18519678
MAPK1	MAPK14	No	in vitro	12697810 , 17255949
MAPK1	KSR1	No	in vivo	9858547
MAPK1	MAP2K2	No	in vitro;in vivo;yeast 2-hybrid	11823456 , 11134045
MAPK1	SMAD2	No	in vitro	10197981

Gene Report

Literature-origin GO terms

Gene mapped GO terms

Literature-origin KEGG pathway

Gene mapped KEGG pathways

Gene mapped BioCarta pathways

Gene mapped Reactome pathways