Gene Report

Basic Information

Approved Symbol	CALM2
Approved Name	calmodulin 2 (phosphorylase kinase, delta)
Symbol Alias	PHKD, CAMII
Name Alias	"prepro-calmodulin 2"
Location	2p21.3-p21.1
Position	chr2:47403858-47404229 (-)
External Links	Entrez Gene: 805 Ensembl: ENSG00000143933 UCSC: uc002rvt.2 HGNC ID: 1445
No. of Studies (Positive/Negative)	1(1/0)
Type	Literature-origin

Positive relationships between CALM2 and MDD (count: 1)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
CALM2	Kang HJ, 2012	patients and normal controls		Here we use microarray gene profiling and electron microscop...... Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function-related genes (CALM2, SYN1, RAB3A, RAB4B and TUBB4) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD More...

Positive relationships between CALM2 and other components at different levels (count: 0)

Positive relationship network of CALM2 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 CALM2 and MDD (count: 0)

Negative relationships between CALM2 and other components at different levels (count: 0)

CALM2 related SNPs in MK4MDD (count: 0)

CALM2 related proteins in MK4MDD (count: 0)

CALM2 related GO terms (count: 87)

ID	Name	Type	Evidence
Literature-origin GO terms
GO:0007268	synaptic transmission	biological process	TAS
GO:0000165	MAPK cascade	biological process	TAS

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0046209	nitric oxide metabolic process	biological process	TAS
GO:0070062	extracellular exosome	cellular component	IDA[20458337\|23376485]
GO:0051592	response to calcium ion	biological process	IDA[7607248]
GO:0060315	negative regulation of ryanodine-sensitive calcium-release channel activity	biological process	ISS
GO:0031997	N-terminal myristoylation domain binding	molecular function	IPI[15632291]
GO:0005886	plasma membrane	cellular component	TAS[10899953]
GO:0043647	inositol phosphate metabolic process	biological process	TAS
GO:0030168	platelet activation	biological process	TAS
GO:1901844	regulation of cell communication by electrical coupling involved in cardiac conduction	biological process	IC
GO:0007265	Ras protein signal transduction	biological process	TAS
GO:0006006	glucose metabolic process	biological process	TAS
GO:0010880	regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	biological process	IDA[20226167]
GO:0071902	positive regulation of protein serine/threonine kinase activity	biological process	TAS[20668654]
GO:0051412	response to corticosterone	biological process	IEA
GO:0048010	vascular endothelial growth factor receptor signaling pathway	biological process	TAS
GO:0044325	ion channel binding	molecular function	IPI[21167176\|23040497]
GO:0007173	epidermal growth factor receptor signaling pathway	biological process	TAS
GO:0044281	small molecule metabolic process	biological process	TAS
GO:0030801	positive regulation of cyclic nucleotide metabolic process	biological process	IDA[8631777]
GO:0005975	carbohydrate metabolic process	biological process	TAS
GO:0051000	positive regulation of nitric-oxide synthase activity	biological process	IEA
GO:0008543	fibroblast growth factor receptor signaling pathway	biological process	TAS
GO:0008179	adenylate cyclase binding	molecular function	IEA
GO:0035307	positive regulation of protein dephosphorylation	biological process	IDA[8631777]
GO:0019904	protein domain specific binding	molecular function	IPI[11984006]
GO:0050999	regulation of nitric-oxide synthase activity	biological process	TAS
GO:0007165	signal transduction	biological process	TAS
GO:0000186	activation of MAPKK activity	biological process	TAS
GO:0005980	glycogen catabolic process	biological process	TAS
GO:0030017	sarcomere	cellular component	IDA[20226167]
GO:0061024	membrane organization	biological process	TAS
GO:0005813	centrosome	cellular component	IDA[16760425]
GO:0005576	extracellular region	cellular component	TAS
GO:0048011	neurotrophin TRK receptor signaling pathway	biological process	TAS
GO:0007186	G-protein coupled receptor signaling pathway	biological process	TAS[10899953]
GO:0005509	calcium ion binding	molecular function	IDA[7607248\|8631777\|11286509\|23040497]; ISS
GO:0045087	innate immune response	biological process	TAS
GO:0007264	small GTPase mediated signal transduction	biological process	TAS
GO:0007596	blood coagulation	biological process	TAS
GO:0031996	thioesterase binding	molecular function	IPI[16127172]
GO:0055117	regulation of cardiac muscle contraction	biological process	IMP[23040497]
GO:0031954	positive regulation of protein autophosphorylation	biological process	TAS[20668654]
GO:0031432	titin binding	molecular function	IPI[7607248]
GO:0007190	activation of adenylate cyclase activity	biological process	IEA
GO:0008286	insulin receptor signaling pathway	biological process	TAS
GO:0060316	positive regulation of ryanodine-sensitive calcium-release channel activity	biological process	IDA[20226167]
GO:0043274	phospholipase binding	molecular function	IPI[12821674]
GO:0050998	nitric-oxide synthase binding	molecular function	IEA
GO:0005737	cytoplasm	cellular component	TAS[10899953]
GO:0005654	nucleoplasm	cellular component	TAS
GO:0002576	platelet degranulation	biological process	TAS
GO:0005513	detection of calcium ion	biological process	IMP[23040497]
GO:0002027	regulation of heart rate	biological process	IMP[23040497]
GO:0007411	axon guidance	biological process	TAS
GO:0030426	growth cone	cellular component	IEA
GO:0010881	regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	biological process	IC
GO:0005829	cytosol	cellular component	TAS
GO:0000922	spindle pole	cellular component	IDA[16760425]
GO:0016056	rhodopsin mediated signaling pathway	biological process	TAS
GO:0021762	substantia nigra development	biological process	IEP[22926577]
GO:0002223	stimulatory C-type lectin receptor signaling pathway	biological process	TAS
GO:0006936	muscle contraction	biological process	TAS
GO:0007202	activation of phospholipase C activity	biological process	TAS
GO:0007603	phototransduction, visible light	biological process	TAS
GO:0048306	calcium-dependent protein binding	molecular function	IEA
GO:0032516	positive regulation of phosphoprotein phosphatase activity	biological process	IDA[8631777]
GO:0001975	response to amphetamine	biological process	IEA
GO:0034704	calcium channel complex	cellular component	IDA[23040497]
GO:0010801	negative regulation of peptidyl-threonine phosphorylation	biological process	TAS[20668654]
GO:0030235	nitric-oxide synthase regulator activity	molecular function	IEA
GO:0038095	Fc-epsilon receptor signaling pathway	biological process	TAS
GO:0019901	protein kinase binding	molecular function	IPI[20668654]
GO:1901841	regulation of high voltage-gated calcium channel activity	biological process	IEA
GO:0043548	phosphatidylinositol 3-kinase binding	molecular function	IEA
GO:0051343	positive regulation of cyclic-nucleotide phosphodiesterase activity	biological process	IDA[8631777]
GO:0010800	positive regulation of peptidyl-threonine phosphorylation	biological process	TAS[20668654]
GO:0005876	spindle microtubule	cellular component	IDA[16760425]
GO:0043539	protein serine/threonine kinase activator activity	molecular function	TAS[20668654]
GO:0072542	protein phosphatase activator activity	molecular function	IDA[8631777]
GO:0005515	protein binding	molecular function	IPI[3111527\|7607248\|10692436\|10880439\|11807546\|11807557\|12577052\|14594800\|14960328\|14978283\|15063758\|15140941\|15161933\|15719022\|16189514\|16478480\|16512683\|16760425\|16799092\|17568776\|17582331\|17620599\|17719545\|18567582\|18570893\|19632986\|20029029\|20103772\|2
GO:0032465	regulation of cytokinesis	biological process	IMP[16760425]
GO:0005634	nucleus	cellular component	IDA[21630459]
GO:0031800	type 3 metabotropic glutamate receptor binding	molecular function	IEA
GO:0022400	regulation of rhodopsin mediated signaling pathway	biological process	TAS
GO:0031982	vesicle	cellular component	IDA[19190083]

CALM2 related KEGG pathways (count: 12)

ID	Name	Brief Description	Full Description
Literature-origin KEGG pathway
hsa04070	phosphatidylinositol signaling_system	Phosphatidylinositol signaling system
hsa04020	calcium signaling_pathway	Calcium signaling pathway	Ca2+ that enters the cell from the outside is a principal so...... Ca2+ that enters the cell from the outside is a principal source of signal Ca2+. Entry of Ca2+ is driven by the presence of a large electrochemical gradient across the plasma membrane. Cells use this external source of signal Ca2+ by activating various entry channels with widely different properties. The voltage-operated channels (VOCs) are found in excitable cells and generate the rapid Ca2+ fluxes that control fast cellular processes. There are many other Ca2+-entry channels, such as the receptor-operated channels (ROCs), for example the NMDA (N-methyl-D-aspartate) receptors (NMDARs) that respond to glutamate. There also are second-messenger-operated channels (SMOCs) and store-operated channels (SOCs). The other principal source of Ca2+ for signalling is the internal stores that are located primarily in the endoplasmic/sarcoplasmic reticulum (ER/SR), in which inositol-1,4,5-trisphosphate receptors (IP3Rs) or ryanodine receptors (RYRs) regulate the release of Ca2+. The principal activator of these channels is Ca2+ itself and this process of Ca2+-induced Ca2+ release is central to the mechanism of Ca2+ signalling. Various second messengers or modulators also control the release of Ca2+. IP3, which is generated by pathways using different isoforms of phospholipase C (PLCbeta, delta, epsilon, gamma and zeta), regulates the IP3Rs. Cyclic ADP-ribose (cADPR) releases Ca2+ via RYRs. Nicotinic acid adenine dinucleotide phosphate (NAADP) may activate a distinct Ca2+ release mechanism on separate acidic Ca2+ stores. Ca2+ release via the NAADP-sensitive mechanism may also feedback onto either RYRs or IP3Rs. cADPR and NAADP are generated by CD38. This enzyme might be sensitive to the cellular metabolism, as ATP and NADH inhibit it. The influx of Ca2+ from the environment or release from internal stores causes a very rapid and dramatic increase in cytoplasmic calcium concentration, which has been widely exploited for signal transduction. Some proteins, such as troponin C (TnC) involved in muscle contraction, directly bind to and sense Ca2+. However, in other cases Ca2+ is sensed through intermediate calcium sensors such as calmodulin (CALM). More...
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
hsa04740	olfactory transduction	Olfactory transduction	Within the compact cilia of the olfactory receptor neurons (...... Within the compact cilia of the olfactory receptor neurons (ORNs) a cascade of enzymatic activity transduces the binding of an odorant molecule to a receptor into an electrical signal that can be transmitted to the brain. Odorant molecules bind to a receptor protein (R) coupled to an olfactory specific Gs-protein (G) and activate a type III adenylyl cyclase (AC), increasing intracellular cAMP levels. cAMP targets an olfactory-specific cyclic-nucleotide gated ion channel (CNG), allowing cations, particularly Na and Ca, to flow down their electrochemical gradients into the cell, depolarizing the ORN. Furthermore, the Ca entering the cell is able to activate a Ca-activated Cl channel, which would allow Cl to flow out of the cell, thus further increasing the depolarization. Elevated intracellular Ca causes adaptation by at least two different molecular steps: inhibition of the activity of adenylyl cyclase via CAMKII-dependent phosphorylation and down-regulation of the affinity of the CNG channel to cAMP.Longer exposure to odorants can stimulate particulate guanylyl cyclase in cilia to produce cGMP and activate PKG, leading to a further increase in amount and duration of intracellular cAMP levels, which may serve to convert inactive forms of protein kinase A (PKA2) to active forms (PKA*). As part of a feedback loop, PKA can inhibit the activation of particulate guanylyl cyclase. 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...
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...
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...
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...
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...
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...
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...
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...

CALM2 related BioCarta pathways (count: 20)

ID	Name	Brief Description	Full Description
Literature-origin BioCarta pathway
TCR_PATHWAY	tcr pathway	T Cell Receptor Signaling Pathway	The T Cell Receptor plays a key role in the immune system. T...... The T Cell Receptor plays a key role in the immune system. The specificity of the receptor is governed by the binding site formed from the mature alpha and beta chains (shown here) or gamma and delta chains in gamma/delta T Cells. It is the ability of this receptor to bind a complex of foreign peptide in the groove of an MHC molecule that leads to T cell activation. Upon activation the T cell can assist in activating other cells or carry out cytolytic attacks depending on the particular T cell type. The CD3 complex and CD4 (Th cells) or CD8 (Tc cells) work to transmit the activation signal to the T cell's transcriptional machinary upon engagement of the receptor. More...

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
GCR_PATHWAY	gcr pathway	Corticosteroids and cardioprotection	Myocardial infarction damages heart tissue both during the i...... Myocardial infarction damages heart tissue both during the initial ischemia and the subsequent reperfusion of tissues with oxygen. Corticosteroids can protect cardiac tissue from damage following a heart attack, but the mechanisms by which corticosteroids are cardioprotective have not been clear and negative side effects such as reduced wound healing may result from their use. Corticosteroids exert a variety of actions through binding to the glucocorticoid receptor (GR), a member of the steroid hormone receptor gene family. GR acts as a ligand-dependent transcription factor, but some of the cardioprotective effects mediated by GR-bound corticosteroids are non-transcriptional in nature. Glucocorticoids are commonly used as anti-inflammatory drugs in a variety of conditions, and some of their effects in the heart result from inhibition of the inflammatory response of heart tissue to ischemia and reperfusion. NF-kB is a transcription factor involved in signaling by inflammatory factors such as TNF, and is repressed by glucocorticoids. Annexin-1 is a calcium-dependent phospholipid binding protein whose expression is induced by corticosteroids and inhibits the infiltration of neutrophils into tissue, blocking reperfusion-induced inflammatory heart damage. A non-transcriptional cardioprotective effect of glucocorticoids is activation of NO production by endothelial nitric oxide synthase (eNOS). Glucocorticoids activate eNOS through activation of PI3 kinase and AKT and increased NO produced by eNOS can diffuse into surrounding tissues to prevent clotting and cause vasodilation. The beta-2 adrenergic receptor can also activate PI3 kinase and may synergize with glucocorticoids in this pathway. The atrial natriuretic factor (ANF) is a peptide secreted by the atrial wall in response to increased atrial pressure such as occurs during cardiac failure and to be decreased by myocardial infarction. Glucocorticoids increase the secretion of ANF by acting at the transcriptional level to increase expression of the pro-ANF peptide, perhaps inducing increased water excretion in the kidneys to reduce blood volume and reduce atrial pressure. The exploration of glucorticoid responses may allow the identification of compounds that retain the cardioprotective activities but do not inhibit wound healing. Alternative mechanisms of eNOS activation may also provide a route to identify cardioprotective drugs. 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...
NO1_PATHWAY	no1 pathway	Actions of Nitric Oxide in the Heart	Nitric oxide (NO) has a number of important physiological ac...... Nitric oxide (NO) has a number of important physiological actions in the cardiovascular system. In the heart, NO plays role in keeping the vessels patent via vasodilation and prevention of platelet aggregation. It also plays an important role in regulating the force and rate of contraction. In vivo NO is released by shear stress of ligands that increase intracellular Ca2+ in endothelial cells. The increase intracellular Ca2+ activates nitric oxide synthase III (NOSIII) by promoting the binding of Ca/Calmodulin to the enzyme. NOSIII, which is resident in the Golgi complex, is transported together with caveolin-1 to the caveolae at the plasma membrane via vesicles. Shear stress signals via a potassium channel and the cytoskeleton, which results in tyrosine phosphorylation of specific proteins, activation of phosphatidylinositol 3-kinase, and subsequently in activation of Akt kinase. Akt activation by shear stress but also by VEGF activates NOSIII by serine phosphorylation, which increases the affinity of NOSIII for calmodulin. After agonist binding at the plasma membrane, NOSIII-activating receptors translocate to caveolae. VEGF receptor signals via its tyrosine kinase domain. Furthermore, agonist receptors activate calcium channels of the endoplasmic reticulum (ER) via phospholipase C and inositol 1,4,5-trisphosphate. This calcium flux induces binding of calmodulin to NOSIII, whereas the NOSIII-caveolin-1 interaction is disrupted. At the same time, NOSIII is translocated into the cytosol. On binding of calmodulin, NOSIII generates NO, is enhanced by the interaction with Hsp90. Once activated, NOSIII catabolizes L-arginine to NO, which diffuses out of the cell. NO stimulates guanylate (G-) cyclase and increases cGMP levels. cGMP activates cGMP-dependent protein kinase (PKG), cGMP-inhibited phosphodiesterase (PDEIII), and cGMP-stimulated phosphodiesterase (PDEII). PKG may reduce the force and rate of contraction, possibly by phosphorylating troponin I or by phosphorylating phospholamban. PDEIII is inhibited by the increases in cGMP brought about by NO. This may result in an increase in cAMP and cAMP-dependent protein kinase (PKA). PKA in turn activates Ca2+ channels, countering the effects of PKG. In contrast, cGMP may stimulate PDEII, reduce cAMP levels and PKA activity, and thereby reduce Ca2+ channel activity. Ach, acetylcholine. CAT-1, cationic amino acid transporter. More...
GPCR_PATHWAY	gpcr pathway	Signaling Pathway from G-Protein Families	G-aS-coupled receptors stimulate adenylyl cyclase (AC), whic...... G-aS-coupled receptors stimulate adenylyl cyclase (AC), which synthesizes cAMP from ATP. In contrast Gai-coupled receptors inhibit AC and so reduce cAMP formation. The bg subunits from Gai and other G proteins are able to activate the MAP kinase pathways and PLCb. GPCRs coupled to the Gaq family of G proteins stimulate PLCb, which cleaves membrane phospholipids to produce IP3, which mobilizes intracellular calcium, and DAG, which activates PKC. Second messenger pathways then activate a range of effector systems to change cell behaviour; in many cases this includes the regulation of gene transcription. Dotted line shows a more indirect pathway. More...
CACAM_PATHWAY	cacam pathway	Ca++/ Calmodulin-dependent Protein Kinase Activation	The calcium/calmodulin-dependent kinases (CaMKs) are involve...... The calcium/calmodulin-dependent kinases (CaMKs) are involved in a large number of cellular responses induced by hormones, neurotransmitters and other signalling. Elevation of calcium functions as a major second messenger, where the intracellular concentration of calcium can be maintained at extremely low levels and susequently increased following specific calcium-mobilizing stimuli. There are many buffers to the calcium fluxuations including membrane pumps and calcium-binding proteins that create discrete spatial control of its effectors and their targets. The current family of multifunctional calcium/calmodulin (CaM)-dependent protein kinases (CaMKs) consists of CaMKI, CaMKII and CaMKIV. These kinases translate and co-ordinate the calcium fluxuations into the appropriate cellular responses via phosphorylation. These kinases are partially regulated by the intracellular calcium receptor calmodulin (CaM), have common as well as unique features in their structure, regulation and activation. CaMKII, CaMKI and CaMKIV, have an autoregulatory domain that restricts or inhibits enzymic activity in the absence of calcium/CaM. Calcium/CaM binding alone produces maximal activity of CaMKII, whereas CaMKI and CaMKIV have an activation loop that requires phosphorylation of a threonine residue by CaMK kinase (CaMKK) for maximal activity. Two genes (alpha and beta) for CaMKK, which is also regulated by CaM, have been identified. The highest expression of these isoforms occurs in the brain but the activity of the CaMKs has been identified in most cell types. CaMKIV has a post-calmodulin autophosphorylation step that is not observed in CaMKI. The CaMKII multimer can autophosphorylate either the autoregulatory domain or the CaM-binding domain, producing diverse effects in its regulation and sensitivity to Calcium/CaM. Autophosphorylation of CaMKII can produce Calcium/CaM- independent activity (autonomous activity), without affecting its maximal Calcium/CaM-stimulated activity. The CaMKII autophosphorylation involves a kinase cascade of sorts, with each subunit of the multimeric enzyme acting as both kinase and kinase kinase. Autophosphorylation establishes a 1000-fold increase in the affinity for its activator Calcium/CaM (also known as CaM trapping); however, autophosphorylation within the CaM-binding domain following CaM dissociation of activated/autophosphorylated enzyme restricts or prevents CaM from rebinding (CaM capping). The mechanisms and consequences of autophosphorylation are central to the CaMKII enzyme's complex regulatory behavior enabling it to become differentially activated at different frequencies and levels of calcium spikes. The target proteins for the CaMKs are very similar. An example target of the CaMKs is the transcriptional activating protein CREB. The phosphorylation states of CREB after CaMK phosphorlyation differ by the additional phosphorylation of CREB at serine 142 that functions as an additional inhibitory site. This difference appears to be the result of adjacent amino acids. More...
HDAC_PATHWAY	hdac pathway	Control of skeletal myogenesis by HDAC and calcium/calmodulin-dependent kinase (CaMK)	The differentiation of muscle cells is transcriptionally reg...... The differentiation of muscle cells is transcriptionally regulated, in part by the myocyte enhancer factor-2, MEF2. During myogenesis MEF2 binds to MyoD and other basic helix-loop-helix factors to activate transcription of genes involved in muscle cell differentiation. Transcriptional activation by MEF2 is blocked by interaction with HDAC5 and other histone deacetylases. In undifferentiated myoblasts, HDAC5 is present in the nucleus where it binds to MEF2 to block activation of muscle genes. When activated by IGF-1 signaling, CaM kinase phosphorylates HDAC proteins, causing them to be exported from the nucleus, releasing the block on MEF2 transcriptional activation and allowing differentiation to proceed. Transcription cofactors also interact with MEF2 to contribute to gene regulation and myogenesis. The transcriptional regulator NFAT, for example, acts as a cofactor for MEF2 when calcium and calcineurin signaling activate it. There are four members of the Mef2 gene family, Mef2a-2d. Mef2a is expressed in brain, heart and skeletal muscle. Mef2c is involved in myogenesis in cardiac and skeletal muscle. Mef2d is widely expressed, and may be involved in the regulation of T cell function as well as muscle. Several factors regulate Mef2 transcription factors, including Map kinases and histone deacetylase (HDAC) enzymes. Mef2 is phosphorylated by p38 map kinase, and phosphorylation of Mef2c by p38 contributes to skeletal muscle differentiation. BMK-1 (also called Erk5) is another member of the Map kinase family that regulates the activity of Mef2 family members and is unique in that it appears itself to possess a transcriptional activation domain and act as a transcriptional coactivator. Mekk3 disruption prevented normal cardiovascular development in mice and appears to signal through p38 and Mef2c in normal cardiovascular development. More...
NOS1_PATHWAY	nos1 pathway	Nitric Oxide Signaling Pathway	Glutamatergic-mediated nitric oxide (NO) production occurs v...... Glutamatergic-mediated nitric oxide (NO) production occurs via the N-methyl-D-aspartic acid (NMDA) postsynaptic density protein 95 (PSD95)-neuronal nitric oxide synthase (NOS1) ternary complex. The increased intracellular Ca2+ stimulates the interaction of nNOS and calmodulin (CaM) and the translocaton of nNOS from the plasma membrane to the cytoplasm. The dephosphorylation of nNOS by Calcineurin catalyzes the conversion of arginine to citrulline and nitric oxide (NO), which turns on guanylate cyclase and the various cGMP regulated signaling pathways. 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...
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...
NDKDYNAMIN_PATHWAY	ndkdynamin pathway	Endocytotic role of NDK, Phosphins and Dynamin	Reliable neurotransmitter release requires the presence of s...... Reliable neurotransmitter release requires the presence of sufficent numbers of synaptic vesicles. The process of synaptic vesicle endocytosis (SVE) is coordinated by a group of proteins called dephosphins. The current set of seven known dephosphins are nerve treminal proteins with little or no structural hoimology but satisfy two essential criteria: they are essential for SVE and they are rapidly and coordinately dephosphorlyated in response to a calcium influx through voltage-dependent calicium channels. The calicium signal is mediated by calmodulin (CaM) and calcineurin. Each dephosphin plays an essential role in overlapping phases or segments of the cycle. The four phases of SVE are nucleation, invagination, fission and uncoating. In this diagram the internalization of the vesicle is the uncoating step. In order to illustrate the complexity of this process the initial display of the protein is labelled with a name and a number. This number is then used at the decloaking or uncoating step to show the release and seperation of the various factors. Each step in the process has a different set of complex components. The components are shown in highlighted boxes above. The nucleation phase initiates with the activation of CaM/Calcineurin and the subsequent dephosphorylation of AP180. AP180 and clathrin are then recruited to the membrane by AP2 and PtdIns(4,5)P2 (comma shaped molecule in the diagram). Nucleation is completed by the addition of epsin and eps15. Invagination proceeds with the formation of the amphiphysin1/2 heterodimer and its addition to the maturing vesicle surface complexes. The final components, dynamin and synaptojanin, are recruited to the budding vesicle by the amphiphysin1/2 heterodimer. Dynamin forms a complete ring around the vesicle neck and completes fission via its PtdIns(4,5)P2 stimulated GTPase activity. After internalization the vesicle is quickly uncoated, in a process believed to be mediated by synaptojanin, and is accompnied by the disassembly of clathrin. 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...
MEF2D_PATHWAY	mef2d pathway	Role of MEF2D in T-cell Apoptosis	Mef2 pathway. Mef2 pathway.
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...
CCR5_PATHWAY	ccr5 pathway	Pertussis toxin-insensitive CCR5 Signaling in Macrophage	The chemokine receptors CCR5 and CXCR4 in macrophages are ac...... The chemokine receptors CCR5 and CXCR4 in macrophages are activated by their peptide ligands and also by the HIV envelope protein GP120 during HIV infection. One mechanism of signaling by these GPCRs is through activation of Gi signaling. These chemokine receptors can also signal through a Gi-independent pertussis toxin-insensitive pathway. This pathway elevates calcium influx into the cell through CRAC channels, ion channels that are activated by calcium release. Elevated calcium from CRAC is required for downstream activation of Pyk2, a focal adhesion-associated protein kinase. Non Gi signaling by these chemokine receptors also involves the Jnk and p38 Map kinase pathways leading to AP-1 activation and activation of genes such as MIP-1 and MCP-1. This pathway may be involved in the role of macrophages in the pathogenesis of AIDS. More...
PGC1A_PATHWAY	pgc1a pathway	Regulation of PGC-1a	Peroxisome proliferator-activated receptor gamma coactivator...... Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) is a tissue-specific coactivator that enhances the activity of many nuclear receptors and coordinates transcriptional programs important for energy metabolism and energy homeostasis. Inappropriate increases in PGC-1a activity have been linked to a number of pathological conditions including heart failure and diabetes. PGC-1a is highly expressed in metabolically active tissues including brown fat, skeletal muscle and heart. PGC-1a has been implicated in mitochondrial biogenesis in the heart and increased mitochondrial respiration in brown fat. PGC-1a is a coactivator for many factors including, CBP, Scr-1, PPARa, GR (glucocorticoid receptor), THR (thyroid hormone receptor), several orphan receptors and MEF2. This pathway illustrates two of the cofactor regulatory factors MEF2 and PPARa) and an example orphan receptor feedback inhibition loop. Glut4 is used as an example of the downstream elements leading to changes in metabolism. Ichida et al discovered the ERRa repression of PGC-1a. Their results suggest a novel mechanism of transcriptional control wherein ERR-a can function as a specific molecular repressor of PGC-1a. This suggests that other co-activators might also have specific repressors, adding another layer of combinatorial complexity in transcriptional regulation. Czubryt et al identified PGC-1 a as a key target of the MEF2/HDAC regulatory pathway and demonstrated this pathway's importance in maintenance of cardiac mitochondrial function. The linking of MEF2/HDAC provides an potential explanation for the increase in mitochondrial number observed in response to CaMK signaling. More...
BCR_PATHWAY	bcr pathway	BCR Signaling Pathway	Significant progress has been made towards delineation of th...... Significant progress has been made towards delineation of the intrinsic molecular processes that regulate B lymphocyte immune function. Recent observations have provided a clearer picture of the interactive signaling pathways that emanate from the mature B cell antigen receptor (BCR) complex and the different precursor complexes that are expressed during development. Studies have also revealed that the net functional response to a given antigenic challenge is affected by the combined action of BCR-dependent signaling pathways, as well as those originating from various coreceptors expressed by B cells (e.g. CD19, CD22, FcgRIIb and PIR-B). It is now well established that reversible tyrosine phosphorylation plays an important role in regulating B cell biology. In particular, binding of antigen to the BCR promotes the activation of several protein tyrosine kinases (PTK) that, in conjunction with protein tyrosine phosphatases (PTP), alter the homeostasis of reversible tyrosine phosphorylation in the resting B cell. The net effect is a transient increase in protein tyrosine phosphorylation that facilitates the phosphotyrosine dependent formation of effector protein complexes, promotes targeting of effector proteins to specific microenvironments within the B cell and initiates the catalytic activation of downstream effector proteins. Studies have demonstrated that Src family PTKs are activated initially and serve to phosphorylate CD79a and CD79b thereby creating phosphotyrosine motifs that recruit downstream signaling proteins. In particular, phosphorylation of the BCR complex leads to the recruitment and activation of the PTK Syk, which in turn promotes phosphorylation of PLCg, Shc and Vav. Additionally, the Tec family member Btk is recruited to the plasma membrane where it is involved in activation of PLCg. Initiation of B lymphocyte activation is dependent on the tyrosine phosphorylation-dependent formation of multi-molecular effector protein complexes that activate downstream signaling pathways. The formation of such complexes was initially hypothesized to occur primarily via effector protein binding to the BCR complex itself. However, recent studies have demonstrated that productive signaling via the BCR is in fact dependent on tyrosine phosphorylation of one or more adapter proteins that play a crucial role in recruitment and organization of effector proteins at the plasma membrane. The SLP-65/BLNK adapter protein has recently been shown to play a crucial role in recruitment and activation of key signal transducing effector proteins in the B cell. After the BCR has been engaged by antigen and the activation response has been initiated, numerous second messengers and intermediate signal transducing proteins are activated. These include the production of lipid second messengers by phosphatidylinositol 3-kinase, and the PLC-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate to yield diacylglycerol and 1,4,5-inositoltrisphosphate (IP3). DAG is important for activation of PKC whereas IP3 promote release of calcium from the endoplasmic reticulum and the subsequent influx Ca2+ from the extracellular space. Numerous intermediate signaling proteins are also activated including the Ras and Rap1, which are small molecular weight GTPases and these ultimately lead to the activation of MAP kinases including Erk, JNK and p38. The net effect of second messenger production and activation of intermediate signaling proteins is the concerted regulation of several transcription factors that mediate gene transcription in the B cell. More...
CALCINEURIN_PATHWAY	calcineurin pathway	Effects of calcineurin in Keratinocyte Differentiation	The differentiation of keratinocytes constantly replenishes ...... The differentiation of keratinocytes constantly replenishes the upper layers of human skin we lose each day. One factor that contributes to terminal keratinocyte differentiation is increased levels of intracellular calcium. Adding calcium to the medium of cultured keratinocytes elevates intracellular calcium and triggers differentiation. Intracellular calcium levels are also increased in response to phospholipase C activation, producing IP3 and releasing calcium from stores in the ER. Intracellular calcium alters multiple signaling pathways, one of which is binding to calmodulin to activate the serine-threonine protein phosphatase calcineurin. Calcineurin dephosphorylates and activates the transcription factor NFAT and both calcineurin and NFAT are expressed in differentiating keratinocytes. Activated NFAT can regulate transcription through binding its own cognate DNA binding site. One marker of keratinocyte differentiation, the p21 gene, is activated by NFAT by a different mechanism, with NFAT activating the p21 promoter by acting as a coactivator for the transcription factors Sp1 and Sp3. Another protein activated by calcium that may be involved in keratinocyte differentiation is protein kinase C (PKC). One substrate of activated PKC is MARCKS (myristoylated alanine-rich kinase C substrate). Phosphorylation of MARCKS by PKC in intact keratinocytes is not induced during calcium-induced differentiation, but does increase when tested in vitro. PKC activity is increased by calcium during keratinocyte differentiation but PKC MARCKS phosphorylation is blocked by the formation of a complex between calmodulin and MARCKS. The immunosuppressants cyclosporin-A (CsA) and FK506 inhibit T cell activation through indirect inhibition of NFAT activation and have several side effects including changes in the skin, suggesting that calcineurin activity may play a role in normal skin physiology. CsA is used to treat psoriasis, a disease involving abnormal proliferation of skin cells. The activity of CsA in treating psoriasis may involve inhibition of immune cells, but may also directly involve inhibition of calcineurin activity in keratinocytes. More...
VIP_PATHWAY	vip pathway	Neuropeptides VIP and PACAP inhibit the apoptosis of activated T cells	Vasoactive intestinal peptide (VIP) and the structurally rel...... Vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP), two neuropeptides present in the lymphoid microenvironment, elicit a broad spectrum of biological functions, including the modulation of innate and adaptive immunity. Another important immunoregulatory function of VIP and PACAP is their inhibition effect on AICD in T cells. They inhibit the TCR-stimulated FasL expression and apoptosis of T cell through specific receptors and induction of intracellular cAMP. VIP down-regulate c-Myc synthesis, the NF-AT-dependent Egr2 and Egr3 expression, the NF-AT and NF-kB. 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...

CALM2 related Reactome pathways (count: 27)

ID	Name	Description
Gene mapped Reactome pathways
REACT_21312	activation of_kainate_receptors_upon_glutamate_binding	Kainate receptors are found both in the presynaptc terminals...... Kainate receptors are found both in the presynaptc terminals and the postsynaptic neurons. Kainate receptor activation could lead to either ionotropic activity (influx of Ca2+ or Na+ and K+) in the postsynaptic neuron or coupling of the receptor with G proteins in the presynaptic and the postsynaptic neurons. Kainate receptors are tetramers made from subunits GRIK1-5 or GluR5-7 and KA1-2. Activation of kainate receptors made from GRIK1 or KA2 release Ca2+ from the intracellular stores in a G protein-dependent manner. The G protein involved in this process is sensitive to pertussis toxin. 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_798	platelet activation	Platelet activation begins with the initial binding of adhes...... Platelet activation begins with the initial binding of adhesive ligands and of the excitatory platelet agonists. Intracellular signaling reactions will then enhance the adhesive and procoagulant properties of tethered platelets or of platelets circulating in the proximity. From the subendothelial adhesive substrates, collagen and possibly vWF are the main inducers of platelet activation. GP VI is the most potent collagen receptor initiating signal generation, an ability derived from its interaction with the FcRI gamma chain. This results in the phosphorylation of the gamma-chain by the non-receptor tyrosine kinases of the Src family. The phosphotyrosine motif is recognized by the SH2 domains of Syk, a tyrosine kinase. This association activates the Syk enzyme, leading to activation. Four PARs are identified, of which PARs 1 ,3 and 4 are substrates for thrombin. PAR 1 is the predominant thrombin receptor, PAR 3 is minimally expressed and PAR 4 is less responsive to thrombin. Platelets do not store PAR1, due to limited protein synthesis, they are capable of responding to thrombin only once. Platelet activation further results in the scramblase-mediated transport of negatively-charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase complex (formed by the activated forms of the blood coagulation factors factor VIII and factor I). More...
REACT_13527	further platelet_releasate	Platelet releasate contains a range of proteins that do not ...... Platelet releasate contains a range of proteins that do not originate in specialized storage granules. In some cases platelet lysis may contribute to the presence of these proteins in the platelet relesate. 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_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_1008	glycogen breakdown_glycogenolysis	Glycogen breakdown occurs via the same chemical steps in all...... Glycogen breakdown occurs via the same chemical steps in all tissues but is separately regulated via tissue specific isozymes and signaling pathways that enable distinct physiological fates for liver glycogen and that in other tissues. Glycogen phosphorylase, which can be activated by phosphorylase kinase, catalyzes the removal of glucose residues as glucose 1-phosphate from the ends of glycogen branches. The final four residues of each branch are removed in two steps catalyzed by debranching enzyme, and further glycogen phosphorylase activity completes the process of glycogen breakdown. The figure shows the actions of phosphorylase and debranching enzyme. The first glucose residue in each branch is released as free glucose; all other residues are released as glucose 1-phosphate. The latter molecule can be converted to glucose 6-phosphate in a step shared with other pathways. More...
REACT_17044	muscle contraction
REACT_15334	darpp32 events	Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARP...... Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), was identified as a major target for dopamine and protein kinase A (PKA) in striatum. Recent advances now indicate that regulation DARPP-32 phosphorylation provides a mechanism for integrating information arriving at dopaminoceptive neurons, in multiple brain regions, via a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones. Activation of PKA or PKG stimulates DARPP-32 phosphorylation at Thr34, converting DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is also phosphorylated at Thr75 by Cdk5, converting DARPP-32 into an inhibitor of PKA. Thus, DARPP-32 has the unique property of being a dual-function protein, acting either as an inhibitor of PP-1 or of PKA. More...
REACT_474	metabolism of_carbohydrates	These pathways together are responsible for: 1) the extracti...... These pathways together are responsible for: 1) the extraction of energy and carbon skeletons for biosyntheses from dietary sugars and related molecules; 2) the short-term storage of glucose in the body (as glycogen) and its mobilization during a short fast; and 3) the synthesis of glucose from pyruvate during extended fasts. More...
REACT_604	hemostasis	Two principal mechanisms limit blood loss after vascular inj...... Two principal mechanisms limit blood loss after vascular injury. Initially, platelets are activated, adhere to the site of the injury, and aggregate into a plug that limits blood loss. Proteins and small molecules released from activated platelets stimulate the plug formation process, and fibrinogen from the plasma forms bridges between activated platelets. These events allow the initiation of the clotting cascade, the second mechanism to limit blood loss. Negatively charged phospholipids exposed on cell surfaces at the site of injury and on activated platelets interact with tissue factor, setting off a cascade of reactions leading to generation of fibrin and the formation of an insoluble fibrin clot that strengthens the platelet plug. More...
REACT_15295	opioid signalling	Opioids are chemical substances similar to opiates, the acti...... Opioids are chemical substances similar to opiates, the active substances found in opium (morphine, codeine etc.). Opioid action is mediated by the receptors for endogenous opioids; peptides such as the enkephalins, the endorphins or the dynorphins. Opioids possess powerful analgesic and sedative effects, and are widely used as pain-killers. Their main side-effect is the rapid establishment of a strong addiction. Opioids receptors are G-protein coupled receptors (GPCR). There are four classes of receptors: mu (MOR), kappa (KOR) and delta (DOR), and the nociceptin receptor (NOP). 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_20558	smooth muscle_contraction	Layers of smooth muscle cells can be found in the walls of n...... Layers of smooth muscle cells can be found in the walls of numerous organs and tissues within the body. Smooth muscle tissue lacks the striated banding pattern characteristic of skeletal and cardiac muscle. Smooth muscle is triggered to contract by the autonomic nervous system, hormones, autocrine/paracrine agents, local chemical signals, and changes in load or length. Actin:myosin cross bridging is used to develop force with the influx of calcium ions (Ca2+) initiating contraction. Two separate protein pathways, both triggered by calcium influx contribute to contraction, a calmodulin driven kinase pathway, and a caldesmon driven pathway. Recent evidence suggests that actin, myosin, and intermediate filaments may be far more volatile then previously suspected, and that changes in these cytoskeletal elements along with alterations of the focal adhesions that anchor these proteins may contribute to the contractile cycle. Contraction in smooth muscle generally uses a variant of the same sliding filament model found in striated muscle, except in smooth muscle the actin and myosin filaments are anchored to focal adhesions, and dense bodies, spread over the surface of the smooth muscle cell. When actin and myosin move across one another focal adhesions are drawn towards dense bodies, effectively squeezing the cell into a smaller conformation. The sliding is triggered by calcium:caldesmon binding, caldesmon acting in an analogous fashion to troponin in striated muscle. Phosphorylation of myosin light chains also is involved in the initiation of an effective contraction. More...
REACT_21322	ionotropic activity_of_kainate_receptors	Kainate receptors are either Ca2+ permeable or impermeable d...... Kainate receptors are either Ca2+ permeable or impermeable depending on the composition of the receptor and the editing status of subunits GluR5 and GluR6 (GRIK1 and 2). More...
REACT_12079	plc gamma1_signalling	The activation of phosphlipase C-gamma (PLC-gamma) and subse...... The activation of phosphlipase C-gamma (PLC-gamma) and subsequent mobilization of calcium from intracellular stores are essential for neurotrophin secretion. PLC-gamma is activated through the phosphorylation by TrkA receptor kinase and this form hydrolyses PIP2 to generate inositol tris-phosphate (IP3) and diacylglycerol (DAG). IP3 promotes the release of Ca2+ from internal stores and this results in activation of enzymes such as protein kinase C and Ca2+ calmodulin-regulated protein kinases. More...
REACT_12508	metabolism of_nitric_oxide	Nitric oxide (NO), a diffusible multifunctional second messe...... Nitric oxide (NO), a diffusible multifunctional second messenger, is implicated in numerous physiological functions in mammals, ranging from immune response and potentiation of synaptic transmission, to dilation of blood vessels and muscle relaxation. NO is synthesized from L-arginine by a family of nitric oxide synthases (NOS). Three NOS isoforms have been characterized: neuronal NOS (nNOS, NOS1) primarily found in neuronal tissue and skeletal muscle; inducible NOS (iNOS, NOS2) originally isolated from macrophages and later discovered in many other cells types; and endothelial NOS (eNOS, NOS3) present in vascular endothelial cells, cardiac myocytes, and in blood platelets. The enzymatic activity of all three isoforms is dependent on calmodulin, which binds to nNOS and eNOS at elevated intracellular calcium levels, while it is tightly associated with iNOS (even at basal calcium levels). As a result, the enzymatic activity of nNOS and eNOS is modulated by changes in intracellular calcium levels, leading to transient NO production, while iNOS continuously releases NO independent of fluctuations in intracellular calcium levels and is mainly regulated at the gene expression level. The NOS enzymes share a common basic structural organization and requirement for substrate cofactors for enzymatic activity. A central calmodulin-binding motif separates an oxygenase (NH2-terminal) domain from a reductase (COOH-terminal) domain. Binding sites for cofactors NADPH, FAD, and FMN are located within the reductase domain, while binding sites for tetrahydrobiopterin (BH4) and heme are located within the oxygenase domain. Once calmodulin binds, it facilitates electron transfer from the cofactors in the reductase domain to heme enabling nitric oxide production. Both nNOS and eNOS contain an additional insert (40-50 amino acids) in the middle of the FMN-binding subdomain that serves as autoinhibitory loop, destabilizing calmodulin binding at low calcium levels and inhibiting electron transfer from FMN to the heme in the absence of calmodulin. iNOS does not contain this insert. Because NOS enzymatic activity is modulated by the presence of its substrates and cofactors within the cell, under certain conditions, NOS may generate superoxide instead of NO, a process referred to as uncoupling (uncoupling of NADPH oxidation and NO synthesis). NO is a highly active molecule that diffuses across cell membranes and cannot be stored inside the producing cell. Its signaling capacity must be controlled at the levels of biosynthesis and local availability. Indeed, NO production by NO synthases is under complex and tight control, being regulated at transcriptional and translational levels, through co- and posttranslational modifications, and by subcellular localization. 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_20	formation of_platelet_plug	Hemostasis is a physiological response that culminates in th...... Hemostasis is a physiological response that culminates in the arrest of bleeding from an injured vessel. Acute vessel injury results in its constriction to reduce the loss of blood. Under normal conditions vascular endothelium supports vasodilation, inhibits platelet adhesion and activation, suppresses coagulation, enhances fibrin cleavage and is anti-inflammatory in character. Under acute vascular trauma vasoconstrictor mechanisms predominate and the endothelium becomes prothrombotic, procoagulatory and proinflammatory in nature. This is achieved by a reduction of endothelial dilating agents: adenosine, NO and prostacyclin; and the direct action of ADP, serotonin and thromboxane on vascular smooth muscle cells to elicit their contraction. The chief trigger for the change in endothelial function that leads to the formation of haemostatic thrombus is the loss of the endothelial cell barrier between blood and ECM components. Circulating platelets identify and discriminate areas of endothelial lesions; here, they adhere to the exposed sub endothelium. Their interaction with the various thrombogenic substrates and locally generated or released agonists results in platelet activation. This process is described as possessing two stages, firstly, adhesion - the initial tethering to a surface, and secondly aggregation - the platelet-platelet cohesion. 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_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_20642	creb phosphorylation_through_the_activation_of_camkii	Ca2+ signal generated through NMDA receptor in the post-syna...... Ca2+ signal generated through NMDA receptor in the post-synaptic neuron activates adenylate cyclase signal transduction, leading to the activation of PKA and phosphorylation and activation of CREB-induced transcription. The isoforms of adenylate cyclase that are activated by Ca2+ in the brain are I, III and IX. More...
REACT_318	platelet degranulation	Platelets function as exocytotic cells, secreting a plethora...... Platelets function as exocytotic cells, secreting a plethora of effector molecules at sites of vascular injury. Platelets contain a number of distinguishable storage granules including alpha granules, dense granules and lysosomes. On activation platelets release a variety of proteins, largely from storage granules but also as the result of apparent cell lysis. These act in an autocrine or paracrine fashion to modulate cell signaling. Alpha granules contain mainly polypeptides such as fibrinogen, von Willebrand factor, growth factors and protease inhibitors that that supplement thrombin generation at the site of injury. Dense granules contain small molecules, particularly adenosine diphosphate (ADP), adenosine triphosphate (ATP), serotonin and calcium, all recruit platelets to the site of injury. More...
REACT_9053	cam pathway	Calmodulin (CaM) is a small acidic protein that contains fou...... Calmodulin (CaM) is a small acidic protein that contains four EF-hand motifs, each of which can bind a calcium ion, therefore it can bind up to four calcium ions. The protein has two approximately symmetrical domains, separated by a flexible hinge region. Calmodulin is the prototypical example of the EF-hand family of Ca2+-sensing proteins. Changes in intracellular Ca2+ concentration regulate calmodulin in three distinct ways. First, by directing its subcellular distribution. Second, by promoting association with different target proteins. Third, by directing a variety of conformational states in calmodulin that result in target-specific activation. Calmodulin binds and activates several effector protein (e.g. the CaM-dependent adenylyl cyclases, phosphodiesterases, protein kinases and the protein phosphatase calcineurin). More...
REACT_20546	ras activation_uopn_ca2_infux_through_nmda_receptor	Ca2+ influx through the NMDA receptor leads to the activatio...... Ca2+ influx through the NMDA receptor leads to the activation of Ras kinase via the activation of RasGRF. More...
REACT_723	glucose metabolism	Glucose is the major form in which dietary sugars are made a...... Glucose is the major form in which dietary sugars are made available to cells of the human body. Its breakdown is a major source of energy for all cells, and is essential for the brain and red blood cells. Glucose utilization begins with its uptake by cells and conversion to glucose 6-phosphate, which cannot traverse the cell membrane. Fates open to cytosolic glucose 6-phosphate include glycolysis to yield pyruvate, glycogen synthesis, and the pentose phosphate pathway. In some tissues, notably the liver and kidney, glucose 6-phosphate can be synthesized from pyruvate by the pathway of gluconeogenesis. More...
REACT_15426	plc beta_mediated_events	The phospholipase C (PLC) family of enzymes is both diverse ...... The phospholipase C (PLC) family of enzymes is both diverse and complex. The isoforms beta, gamma and delta (each have subtypes) make up the members of this family. PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2) into two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellular calcium stores while DAG activates protein kinase C isoforms which are involved in regulatory functions. More...

CALM2 related interactors from protein-protein interaction data in HPRD (count: 28)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
CALM2	MARCKS	Yes	in vitro	12577052
CALM2	MYO6	No	yeast 2-hybrid	16169070
CALM2	ESR2	No	in vivo	11981030
CALM2	PPEF1	No	in vitro;in vivo	12051765
CALM2	DLG1	No	in vitro	12189141
CALM2	MRPL20	No	yeast 2-hybrid	16169070
CALM2	KCNQ3	No	in vitro;in vivo;yeast 2-hybrid	12032157
CALM2	GRM7	No	in vivo	11953448
CALM2	INSR	No	in vitro;in vivo	12153558
CALM2	PCNT	Yes	in vivo	12221128 , 10823944
CALM2	CALD1	Yes	in vivo	11736632
CALM2	MYF5	No	in vitro	10757985
CALM2	KCNQ2	No	in vitro;in vivo;yeast 2-hybrid	12032157
CALM2	GRM5	No	in vivo	9242710 , 11953448
CALM2	NEUROD1	No	in vitro	10757985
CALM2	EGFR	No	in vitro;in vivo	12153558
CALM2	IQCB1	No	in vivo;yeast 2-hybrid	15723066
CALM2	KCNQ5	No	in vitro;in vivo;yeast 2-hybrid	12032157
CALM2	MYF6	No	in vitro	10757985
CALM2	ASCL2	No	in vitro	10757985
CALM2	PPEF2	No	yeast 2-hybrid	12051765
CALM2	EDF1	No	in vitro;in vivo	10816571
CALM2	MYOG	No	in vitro	10757985
CALM2	KIAA1683	No	yeast 2-hybrid	16189514
CALM2	ESR1	Yes	in vivo	11981030
CALM2	MYOD1	No	in vitro	10757985
CALM2	RAB3B	No	in vitro	11741295
CALM2	TCF4	No	in vitro	10757985

Gene Report

Literature-origin GO terms

Gene mapped GO terms

Literature-origin KEGG pathway

Gene mapped KEGG pathways

Literature-origin BioCarta pathway

Gene mapped BioCarta pathways

Gene mapped Reactome pathways