Genes altered in major depressive disorder
Genes altered in major depressive disorder
Positive relationships between JUN and other components at different levels (count: 0)
Positive relationship network of JUN 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
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3. The network is generated using Cytoscape Web
Negative relationships between JUN and MDD (count: 0)
Negative relationships between JUN and other components at different levels (count: 0)
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...
Wnt proteins are secreted morphogens that are required for b......
Wnt proteins are secreted morphogens that are required for basic developmental processes, such as cell-fate specification, progenitor-cell proliferation and the control of asymmetric cell division, in many different species and organs. There are at least three different Wnt pathways: the canonical pathway, the planar cell polarity (PCP) pathway and the Wnt/Ca2+ pathway. In the canonical Wnt pathway, the major effect of Wnt ligand binding to its receptor is the stabilization of cytoplasmic beta-catenin through inhibition of the bea-catenin degradation complex. Beta-catenin is then free to enter the nucleus and activate Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators. Planar cell polarity (PCP) signaling leads to the activation of the small GTPases RHOA (RAS homologue gene-family member A) and RAC1, which activate the stress kinase JNK (Jun N-terminal kinase) and ROCK (RHO-associated coiled-coil-containing protein kinase 1) and leads to remodelling of the cytoskeleton and changes in cell adhesion and motility. WNT-Ca2+ signalling is mediated through G proteins and phospholipases and leads to transient increases in cytoplasmic free calcium that subsequently activate the kinase PKC (protein kinase C) and CAMKII (calcium calmodulin mediated kinase II) and the phosphatase calcineurin.More...
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...
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...
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...
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...
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...
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...
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...
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...
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...
Epithelial cell signaling in Helicobacter pylori infection
Two major virulence factors of H. pylori are the vacuolating......
Two major virulence factors of H. pylori are the vacuolating cytotoxin (VacA) and the cag type-IV secretion system (T4SS) and its translocated effector protein, cytotoxin-associated antigen A (CagA). VacA binds to lipid rafts and glycosylphosphatidylinositol-anchored proteins (GPI-APs) of the target cell membrane. After insertion into the plasma membrane, VacA channels are endocytosed and eventually reach late endosomal compartments, increasing their permeability to anions with enhancement of the electrogenic vacuolar ATPase (v-ATPase) proton pump. In the presence of weak bases, osmotically active acidotropic ions will accumulate in the endosomes. This leads to water influx and vesicle swelling, an essential step in vacuole formation. In addition, it is reported that the VacA cleavage product binds to the tyrosine phosphatase receptor zeta (Ptprz) on epithelial cells and the induced signaling leads to the phosphorylation of the G protein-coupled receptor kinase-interactor 1 (Git1) and induces ulcerogenesis in mice. The other virulence factor cag T4SS mediates the translocation of the effector protein CagA, which is subsequently phosphorylated by a Src kinase. Phosphorylated CagA interacts with the protein tyrosine phosphatase SHP-2, thus stimulating its phosphatase activity. Activated SHP-2 is able to induce MAPK signalling through Ras/Raf-dependent and -independent mechanisms. Deregulation of this pathway by CagA may lead to abnormal proliferation and movement of gastric epithelial cells.More...
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...
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...
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...
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...
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...
TNFR1 (a.k.a. p55, CD120a) is the receptor for TNF(alpha) an......
TNFR1 (a.k.a. p55, CD120a) is the receptor for TNF(alpha) and also will bind TNF(beta). Upon binding TNF(alpha) a TNFR1+ cell is triggered to undergo apoptosis. This critical regulatory process is accomplished by activating the proteolytic caspase cascade that results in the degradation of many critical cellular proteins.More...
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...
The appropriate signaling through the insulin pathway is cri......
The appropriate signaling through the insulin pathway is critical for the regulation of glucose levels and the avoidance of diabetes. Insulin forms a complex with the Insulin Receptor (IR) and b chains to form the active signaling complex. Through recruitment of adaptor molecules and the activation of RAS, the activated IR can cause transcriptional activation.More...
TNF acts on several different signaling pathways through two......
TNF acts on several different signaling pathways through two cell surface receptors, TNFR1 and TNFR2 to regulate apoptotic pathways, NF-kB activation of inflammation, and activate stress-activated protein kinases (SAPKs). Interaction of TNFR1 with TRADD leads to activation of NF-kB and apoptosis pathways, while interaction with TRAF2 has generally been thought to be involved in stress kinase and NF-kB activation but is not required for TNF to induce apoptosis. Activation of NF-kB is mediated by TRAF2 through the NIK kinase and also by RIP but the observation that TNF activates NF-kB in mice lacking TRAF2 indicates that TRAF-2 does not play an essential role in this process. Stress-activated protein kinases, also called JNKs, are a family of map kinases activated by cellular stress and inflammatory signals. Binding of TNF to the TNFR1 receptor activates the germinal center kinase (GCK) through the TNF adaptor Traf2, activating the map kinase MEKK1. Both GCK and MEKK1 interact with Traf2, and GCK is required for MEKK1 activation by TNF, but GCK kinase activity does not appear to be required for MEKK1 activation. Instead, GCK activates MEKK1 by causing MEKK1 oligomerization and autophosphorylation. Tank increases the affinity of Traf2 for GCK to increase Map kinase activation by TNF. Once activated, MEKK1 stands at the top of a map kinase pathways leading to transcriptional regulation, including JNK phosphorylation of c-Jun to stimulate transcriptional activation by AP-1, a heterodimer of c-jun and fos or ATF proteins. The activation of the p38 Map kinase also contributes to AP-1 activation leading to the transcriptional activation of many stress and growth related genes. RIP has been suggested as a component of the p38 pathway in addition to playing a role in NF-kB activation. MEKK1 knockout mice support the role of MEKK1 in JNK activation in some cells but did not support MEKK1 dependent activation of NF-kB. Alternative redundant mechanisms may obscure the role of MEKK1 in NF-kB mechanisms. TNF activation of stress kinase pathways and downstream transcription factors may help to modulate the apoptotic pathways also activated by TNF.More...
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...
The innate immune response responds in a general manner to f......
The innate immune response responds in a general manner to factors present in invading pathogens. Bacterial factors such as lipopolysaccharides (LPS, endotoxin), bacterial lipoproteins, peptidoglycans and also CpG nucleic acids activate innate immunity as well as stimulating the antigen-specific immune response and triggering the inflammatory response. Members of the toll-like receptor (TLR) gene family convey signals stimulated by these factors, activating signal transduction pathways that result in transcriptional regulation and stimulate immune function. TLR2 is activated by bacterial lipoproteins, TLR4 is activated by LPS, and TLR9 is activated by CpG DNA; peptidoglycan recognition protein (PGRP) is activated by peptidoglycan (PGN). The downstream signaling pathways used by these receptors are similar to that used by the IL-1 receptor, activating the IL-1 receptor associated kinase (IRAK) through the MyD88 adaptor protein, and signaling through TRAF-6 and protein kinase cascades to activate NF-kB and Jun. NF-kB and c-Jun activate transcription of genes such as the proinflammatory cytokines IL-1 and IL-12. Several recent reports have suggested that the functional outcomes of signaling via TLR2, TLR4 and PGRP are not equivalent. For example, while the LPS-induced, p38-dependent response was dependent upon PU.1 binding, the PGN-induced, p38 response was not. The intracelular receptor for PGN, PGRP is conserved from insects to mammals. In insects, PGRP activates prophenoloxidase cascade, a part of the insect antimicrobial defense system. Because mammals do not have the prophenoloxidase cascade, its function in mammals is unknown. However, it was suggested that an identical protein Tag7 was a tumor necrosis factor-like (TNF-like) cytokine. PGRP/Tag7 possesses cytotoxicity and triggers intranucleosomal DNA fragmentation in target cells in the same way as many known members of the TNF family. Fragmentation of DNA is one of the characteristics of apoptosis. The possibility that in another system, PGRP/Tag7 would induce NF-kB activation, as observed for TRAIL (TNF-related apoptosis-inducing ligand) receptors canot be ruled out.More...
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...
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...
Interleukin-1 (IL-1) is a pro-inflammatory cytokine that sig......
Interleukin-1 (IL-1) is a pro-inflammatory cytokine that signals primarily through the type 1 IL-1 receptor (IL-1R1). The activities of IL-1 include induction of fever, expression of vascular adhesion molecules, and roles in arthritis and septic shock. The inflammatory activities of IL-1 are partially derived by transcriptionally inducing expression of cytokines such as TNF-alpha and interferons, as well as inducing the expression of other inflammation-related genes. There are two forms of IL-1 encoded by distinct genes, IL-1 alpha and IL-1 beta. IL-1 beta is produced as a 269 amino acid precursor that is cleaved by IL-1beta converting enzyme (ICE) to the active IL-1 beta form that is secreted. IL-1 signaling is opposed by the naturally occurring peptide IL-1 receptor antagonist which is a therapeutic agent for the treatment of arthritis. The type 1 IL-1 receptor protein binds IL-1 beta but requires the IL-1 receptor accessory protein (IL-1RAcP) to transduce a signal. IL-1 binding causes activation of two kinases, IRAK-1 and IRAK-2, associated with the IL-1 receptor complex. IRAK-1 (IL-1 Receptor Associated Kinase) activates and recruits TRAF6 to the IL-1 receptor complex. TRAF6 activates two pathways, one leading to NF-kB activation and another leading to c-jun activation. The TRAF associated protein ECSIT leads to c-Jun activation through the Map kinase/JNK signaling system. TRAF6 also signals through the TAB1/TAK1 kinases to trigger the degradation of I-kB, and activation of NF-kB. The IL-1 signaling cascade represents a highly conserved response to pathogens through evolution, with homologs in insects and even in plants. The signal transduction cascade utilized by IL-1 receptor is similar to that of TNF, resulting in NF-kB activation, and is most similar to that of the Toll-like receptors that also participate in inflammatory signaling responses to pathogen components like endotoxin.More...
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...
Interleukin-6 (IL-6) is a cytokine that provokes a broad ran......
Interleukin-6 (IL-6) is a cytokine that provokes a broad range of cellular and physiological responses. In addition to playing a role in inflammation and hematopoiesis, IL-6 is involved in other processes such as neuronal differentiation and bone loss. To produce these effects IL-6 signals through a receptor composed of two different subunits, an alpha subunit that produces ligand specificity and gp130, a receptor subunit shared in common with other cytokines in the IL-6 family. Binding of IL-6 to its receptor initiates cellular events including activation of JAK kinases and activation of ras-mediated signaling. Activated JAK kinases phosphorylate and activate STAT transcription factors, particularly STAT3, that move into the nucleus to activate transcription of genes containing STAT3 response elements. The ras-mediated pathway, acting through Shc, Grb-2 and Sos-1 upstream and activating Map kinases downstream, activates transcription factors such as ELK-1 and NF-IL-6 (C/EBP-beta) that can act through their own cognate response elements in the genome. These factors and other transcription factors like AP-1 and SRF (serum response factor) that respond to many different signaling pathways come together to regulate a variety of complex promoters and enhancers that respond to IL-6 and other signaling factors.More...
Erythropoietin functions to increase the number of red blood......
Erythropoietin functions to increase the number of red blood cells. Thus, it has found utility as a drug for those needing to replenish erythrocytes for a number of reasons. The signaling mechanism includes multimerization of the receptor upon ligand binding, activation of MAPK cascade, and phosphorylation and activation of Stat5.More...
Hypoxia-Inducible Factor in the Cardiovascular System
Hypoxia (or low O2 levels) affects various pathologies. Firs......
Hypoxia (or low O2 levels) affects various pathologies. First, tissue ischemia, a variation in O2 tension caused by hypoxia/reoxygenation, can lead to endothelial cell changes. For example, long periods of ischemia result in endothelial changes, such as vascular leakage, resulting in varicose veins. In more severe situations, ischemia can lead to myocardial or cerebral infarction and retinal vessel occlusion. Of interest, HIF-1 is stabilized prior to induction of vascular endothelial growth factor (VEGF) expression during acute ischemia in the human heart. Second, pulmonary hypertension associated with chronic respiratory disorders results from persistent vasoconstriction and vascular remodeling. Third, hypoxic gradients created in enlarging solid tumors trigger expression of genes containing hypoxia response element (HRE)s such as those involved in angiogenesis. This allows subsequent delivery of O2, nutrients, and further tumor growth. Vascular remodeling is an important component to tumorigenesis; without proper blood supply, delivery of oxygen may occur by diffusion, but becomes inefficient in tumors greater than 1 mm in diameter. Short-term hypoxia can also elevate platelet numbers, while prolonged exposure may cause some degree of thrombocytopenia in response to increased levels of erythropoetin (EPO). Another disorder involving inadequate responses to hypoxia is preeclampsia, a pathology of pregnancy thought to be caused by improper differentiation of placental trophoblast cells due to poorly controlled O2 tension or improper hypoxia-inducible factor (HIF)-mediated responses. The primary molecular mechanism of gene activation during hypoxia is through HIF-1. Several genes involved in cellular differentiation are directly or indirectly regulated by hypoxia. These include EPO, LDH-A, ET-1, transferrin, transferrin receptor, VEGF, Flk-1, Flt-1, platelet-derived growth factor- (PDGF-), basic fibroblast growth factor (bFGF), and others genes affecting glycolysis. HIF-1 is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors known to induce gene expression by binding to a ~50-bp HRE containing a core 5'-ACGTG-3' sequence. bHLH-PAS proteins heterodimerize to form transcription complexes that regulate O2 homeostasis, circadian rhythms, neurogenesis, and toxin metabolism. Three bHLH-PAS proteins in vertebrates respond to hypoxia: HIF-1 , EPAS (HIF-2 ), and HIF-3. These dimerize with ARNT (aryl hydrocarbon receptor nuclear translocator protein), ARNT-2, or ARNT-3. HIF-1 is ubiquitinated and subsequently degraded in less than 5 minutes under normoxic conditions. Although several candidate O2-sensing molecules have emerged in the literature, the molecular basis of how cells sense O2 levels is poorly characterized. pVHL, the protein product of a tumor-suppressor gene responsible for von Hippel Lindau disease, is implicated in this O2-sensing system by its association with HIF-1 , targeting it for ubiquitin-mediated degradation. Similarly, F-box-containing proteins recognize substrates of the ubiquitin ligases, targeting them for phosphorylation-dependent ubiquitination and proteosomal degradation. In addition to F-boxes, most of these proteins also contain a WD40 or a leucine-rich repeat (LLR) domain that presumably functions as a Ser/Thr binding module. A second family of proteins assisting the ubiquitin ligases share a region designated SOCS-box (originally from the suppressor of cytokine signaling proteins SOCS). Under low O2 (<5% O2) HIF-1 is stabilized leading to the formation of a functional transcription factor complex with ARNT. This complex is the master regulator of O2 homeostasis and induces a network of genes involved in angiogenesis, erythropoiesis, and glucose metabolism.More...
Insulin like growth factor 1 (IGF-1) and its receptor (IGF-1......
Insulin like growth factor 1 (IGF-1) and its receptor (IGF-1R) provide a potent proliferative signaling system that stimulates growth in many different cell types and blocks apoptosis. In vivo IGF-1 acts as an intermediate of many growth hormone responses, and may stimulate the growth of some types of cancer. IGF-1 also provides a mitogenic signal to act as a growth factor for many tissue culture cells. One component of IGF-1 mitogenic signaling is association of the receptor tyrosine kinase with Shc, Grb2, and Sos-1 to activate ras and the Map kinase cascade (raf, Mek, Erk). An endpoint of the Map kinase pathway is modification of transcription factor activity, such as activation of ELK transcription factors. Serum response factor (SRF) and AP-1 contribute to mitogenic signaling by many factors. Phosphorylation of IRS-1 and PI3 kinase activation are also involved in IGF-1 signaling, similar to insulin signaling.More...
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...
Repression of Pain Sensation by the Transcriptional Regulator DREAM
The molecular events that lead to the perception of pain are......
The molecular events that lead to the perception of pain are a key research field in medicine and drug discovery. The opioid receptors modulate pain signaling in response to endogenous peptide ligands and opiate drugs such as morphine. The kappa opioid receptor plays a key role in the profound analgesia of opiates and is activated by the endogenous peptide ligand dynorphin, encoded by the prodynorphin gene. Production of prodynorphin is transcriptionally regulated by a downstream regulatory element (DRE) in the prodynorphin gene. A transcription factor called DREAM (DRE antagonistic modulator) binds to the DRE and represses prodynorphin transcription when bound. DREAM binds calcium with 4 EF-hand motifs and the binding of DREAM to DNA is repressed in the presence of calcium. Many transcription factors are regulated by calcium indirectly through calcium sensitive kinases and phosphatases, but DREAM is unique to date in being a transcription factor that directly binds calcium and is regulated by calcium binding. DREAM may also regulate other genes such as c-fos. DREAM is expressed in spinal cord neurons in regions involved in pain signaling. The regulation of prodynorphin expression by DREAM also leads to the hypothesis that DREAM is involved in pain signaling. Transgenic mice lacking the DREAM gene were unusually pain insensitive and had elevated spinal levels of dynorphin and tonic activation of the kappa opioid receptor, supporting this hypothesis. Other functions of DREAM may exist such as regulation of presenilins and potassium channel activity in the heart. DREAM is also known as calsenilin and KChIP3 through its association with these other proteins. These processes were not affected in mice lacking the DREAM gene however.More...
The epidermal growth factor (EGF) peptide induces cellular p......
The epidermal growth factor (EGF) peptide induces cellular proliferation through the EGF receptor, which has a tyrosine kinase cytoplasmic domain, a single transmembrane domain and an extracellular domain involved in EGF binding and receptor dimerization. Inhibitors of the EGF receptor are being pursued as potential cancer therapies and EGF may stimulate wound healing. Mutation of the EGF receptor has been associated with cancer in humans. The proliferative effects of EGF are signaled through several pathways. Binding of EGF results in EGF receptor dimerization, autophosphorylation of the receptor, and tyrosine phosphorylation of other proteins. The EGF receptor activates ras and the MAP kinase pathway, ultimately causing phosphorylation of transcription factors such as c-Fos to create AP-1 and ELK-1 that contribute to proliferation. Activation of STAT-1 and STAT-3 transcription factors by JAK kinases in response to EGF contributes to proliferative signaling. Phosphatidylinositol signaling and calcium release induced by EGF activate protein kinase C, another component of EGF signaling. Crosstalk of EGF signaling with other pathways make the EGF receptor a junction point between signaling systems.More...
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...
D4-GDI (GDP dissociation inhibitor) is a negative regulator ......
D4-GDI (GDP dissociation inhibitor) is a negative regulator of the ras related Rho Family of GTPases. Since the rho GTPases promote cytoskeletal and membrane changes associated with apoptotic cell death, the removal of the D4-GDI block through its cleavage is important for inducing apoptosis. Caspase-3 cleaves the 28 kDa mature form of D4-GDI to give a 5 kDa and 23 kDa Size fragment. The 23 kDa fragment then translocates to the nucleus. The mechanisms involving cleavage of D4-GDI with apoptosis are not presently known. Activation of the Jun N-Terminal kinase, a regulator of apoptosis, may be one of the mechanisms.More...
Receptors in the TNF receptor family are associated with the......
Receptors in the TNF receptor family are associated with the induction of apoptosis, as well as inflammatory signaling. The Fas receptor (CD95) mediates apoptotic signaling by Fas-ligand expressed on the surface of other cells. The Fas-FasL interaction plays an important role in the immune system and lack of this system leads to autoimmunity, indicating that Fas-mediated apoptosis removes self-reactive lymphocytes. Fas signaling is also involved in immune surveillance to remove transformed cells and virus infected cells. Binding of FAS to oligimerized FasL on another cell activates apoptotic signaling through a cytoplasmic domain termed the death domain that interacts with signaling adaptors including FAF, FADD and DAX to activate the caspase proteolytic cascade. Caspase-8 and caspase-10 are first activated, to then cleave and activate downstream caspases, and a variety of cellular substrates that lead to cell death. Caspases cleave nuclear lamins, causing the nucleus to break down and lose its normal structure and another caspase substrate is DFF, inducing cleavage and degradation of the genome. Other caspase substrates are involved in cytoskeletal structure, cell cycle regulation and signaling pathways. Activation of JNK kinase, activation of Jun, and production of ceramide may also play roles in Fas-mediated apoptosis. Activation of fas-mediated apoptosis is opposed by I-FLICE and FAP. Viruses and tumors may escape immune surveillance in part through suppression of fas-mediated apoptosis using similar mechanisms.More...
Nerve growth factor (NGF) is one of a family of neurotrophin......
Nerve growth factor (NGF) is one of a family of neurotrophins that induce the survival and proliferation of neurons. In cell culture NGF induces the formation of neurite projections and in vivo may stimulate the innervation of tissues. NGF plays a role in the repair, regeneration, and protection of neurons, and as such could serve as a therapeutic agent in neurodegenerative conditions such as Alzheimer's disease. One potential method of NGF application would be through gene therapy or through implantation of cells that have been genetically modified ex vivo. NGF has also been suggested to play a role in other physiological systems and tissues such as the immune system. NGF has two receptors, TrkA and the p75(NTR). NGF may signal its neuroprotective actions through the tyrosine kinase TrkA receptor and trigger apoptosis in some cells through the p75 receptor. High-affinity binding of NGF requires both TrkA and p75(NTR). Binding of NGF to the TrkA receptor causes activation of the receptor tyrosine kinase and downstream signaling cascades. One of the downstream signaling pathways of NGF activates phospholipase C, releasing DAG and IP3 and activating associated downstream pathways such as protein kinase C. Another NGF-activated pathway is the ras-mediated activation of the map kinase pathway. This pathway is initiated through recruitment and activation of Shc, which leads to ras activation through Grb-2 and Sos-1. The Map kinase cascade includes raf, Mek and Erk. The downstream effectors of the ras pathway include activation of fos and jun to form AP-1, activating genes through this transcription factor. Other transcription factors involved in NGF responses include Egr and CREB. The Egr family of transcription factors as well as the Mek/Erk pathway contribute to NGF-induced neurite formation. The CREB family of transcription factors are involved in NGF-induced survival of sympathetic neurons. Further understanding of NGF signaling may be applied to the modulation of NGF responses in neurodegenerative conditions.More...
Platelet Derived Growth Factor (PDGF) plays a critical role ......
Platelet Derived Growth Factor (PDGF) plays a critical role in cellular proliferation and development. The biologically active form is a dimer formed from the A and B chains. PDGF is active to a differing degree depending on which dimer is formed (AA, AB, or BB). The PDGF Receptor (PDGFR) is also a dimer and can form from the combination of the alpha and beta chains in any order (alpha-alpha, alpha-beta, beta-beta). The PDGFR dimer is only formed after ligand binding so the alpha/beta composition of the receptor can be influenced by the form of PDGF that is present. Upon binding of ligand the PDGFR is tyrosine phosphorylated and leads to the phosphorylation of several other cellular proteins.More...
The drug Gleevec (also known as imatinib mesylate or STI-571......
The drug Gleevec (also known as imatinib mesylate or STI-571) was approved by the FDA in 2001 for the treatment of CML, chronic myeloid leukemia. While traditional cytotoxic cancer treatments such as chemotherapy or radiation therapy kill all dividing cells, Gleevec acts on a molecular target by a mechanism that is more specific to cancer cells. Traditional cytotoxic cancer agents have serious side effects such as nausea, weight loss, hair loss and severe fatigue that result from their lack of specificity in killing cells. Gleevec was designed as an inhibitor of a specific receptor associated with CML, and so produces less severe side effects than other cancer agents. CML is associated in most cases with a specific chromosomal defect, a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. This translocation occurs at the site in the genome of a protein tyrosine kinase called abl, creating the abnormal bcr-abl protein, a fusion of the abl gene with another gene called bcr. The kinase activity of abl in the bcr-abl fusion is activated and unregulated, driving the uncontrolled cell growth observed in CML. White blood cells containing the bcr-abl mutation become able to proliferate in the absence of growth factors they normally require. Gleevec inhibits abl kinase activity, helping to reverse uncontrolled cell growth. Gleevec also inhibits the PDGF tyrosine kinase and the c-kit tyrosine kinase. There are a variety of cellular substrates of the bcr-abl kinase that may be involved in cellular transformation. Bcr-abl is associated with the cytoplasm as part of a large signaling complex. Some of the downstream factors in bcr-abl signaling include PI3 kinase/AKT and STAT transcription factors. The activation of bcr-abl also represses apoptosis through induction of anti-apoptosis factors such as Bad, allowing transformed cells to divide. JAK2 kinase activity appears to be one target of bcr-abl. Grb-2 phosphorylation by bcr-abl may play a role in down-regulation of tyrosine kinase signaling. STAT5 may be involved in the failure of apoptosis in bcr-abl cells. In addition to supporting the idea that cancer therapies targeting specific molecular targets should be efficacious with fewer side effects, Gleevec has also demonstrated that drugs inhibiting protein kinases can be developed successfully. Tyrosine kinases are important in a range of cellular processes, including other cancers, and will provide additional drug targets. Gleevec itself has already demonstrated potential in other cancers such as gastrointestinal stromal tumor that do not respond to existing treatments. Although Gleevec has produced very strong clinical responses in patients with early stage CML, patients with late stage disease have had an initial response followed by a relapse of drug resistant CML cells. Cancer cells in patients with Gleevec resistant cancer either had amplification of the bcr-abl gene, or mutation of a key amino acid involved in binding drug from threonine to isoleucine.More...
Terminal differentiation of cells is often accompanied by re......
Terminal differentiation of cells is often accompanied by repression of cellular proliferation, suggesting that there is a mechanism by which these cellular functions are coordinated. Macrophage differentiation is one model system in which this occurs; as macrophages differentiate, they also stop proliferating. Transcriptional regulation plays a key role in cell cycle progression as well as many differentiation processes. Ras stimulates cell cycle progression in part through Ets transcription factors that bind to cell cycle regulatory genes to activate their expression. Ets transcription factors also help to induce early macrophage differentiation. The activation of Ras signaling by M-CSF activates transcription of genes involved in differentiation through the coordinate expression of both Ets factors and AP-1. Other genes involved in cell cycle regulation involved the coordinate action of E2F-1 and Ets transcription factors. Mets is a factor related in sequence to Ets2 that is upregulated during macrophage differentiation. Increased expression of the Mets protein during macrophage differentiation allows the creation of heterodimers with DP103 to act as transcriptional repressors of cell cycle progression genes, recruiting corepressor to promoters they interact with. DP103 is a gene previously identified as an RNA helicase involved in RNA processing that interacts with EBNA factors from Epstein Barr Virus. The transcriptional repression involving Mets with DP103 is selective, and does not involve all Ets regulated genes. While cell cycle genes are repressed by Mets, other gene activated by Ets factors such as those involved in differentiation are not repressed by Mets. The transcriptional repression by Mets also involved members of the Rb family of tumor suppressors, such as p107 and p130. This requirement for additional factors involved in regulating proliferation may allow for another level of control on cell proliferation and coordination with differentiation.More...
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...
Thrombopoietin (TPO) binds to its receptor inducing aggregat......
Thrombopoietin (TPO) binds to its receptor inducing aggregation and activation. TPO signals its growth regulating effects to the cell through several major pathways including MAPK (ERK and JNK), Protein Kinase C, and JAK/Stat.More...
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...
The ataxia telangiectasia-mutated gene (ATM) encodes a prote......
The ataxia telangiectasia-mutated gene (ATM) encodes a protein kinase that acts as a tumor suppressor. ATM activation by ionizing radiation damage to DNA stimulates DNA repair and blocks progression through the cell cycle. Mutation of the ATM gene causes the disease ataxia telangiectasia which which involves an inherited predisposition to some cancers. To play this role ATM interacts with a broad network of proteins, including checkpoint factors (chk1, chk2), tumor suppressors (p53 and BRCA), DNA repair factors (RAD50, RAD51, GADD45), and other signaling molecules (c-Abl and NF-kB). In addition to regulating DNA repair and the cell cycle, ATM can also trigger apoptosis in radiation treated cells.More...
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...
Role of EGF Receptor Transactivation by GPCRs in Cardiac Hypertrophy
One of responses to increased blood pressure is cardiac hype......
One of responses to increased blood pressure is cardiac hypertrophy through increased size of ventricular myocardial cells leading to increased thickness of the ventricular walls. Cardiac hypertrophy allows the heart to handle the increased stress caused by elevated blood pressure but is also a risk factor associated with heart disease. Cardiac hypertrophy results from cross-talk between G-protein coupled receptor signaling and the EGF receptor pathway. Several GPCR ligands are known to stimulate cardiac hypertrophy, including factors that regulate blood pressure such as angiotensin II and endothelin- 1. These factors stimulate phospholipase C through Gq activation, and the production of 1P3 and diacylglycerol second messengers. PKC-delta is activated by DAG and interacts with the metalloproteinase ADAM12. ADAM12 cleaves the membrane-bound HB-EGF to release soluble EGF ligand that activates EGF receptor in myocardial cells. EGF receptor activation downstream through small G proteins and the MAP kinase pathway ultimately leads to cardiac hypertrophy. Signals by GPCR ligands such as angiotensin II result in transcriptional translation of immediate early genes like fos and other genes involved in long-term remodeling of heart tissue and the physiological response to stress in the heart such as the atrial natriuretic factor. Factors such as the AKT kinase, reactive oxygen species (ROS) and NE-kB also are involved in signaling that leads to hypertrophy, although their role is not yet clear. Blocking this pathway at various steps may prevent heart disease through the prevention of cardiac hypertrophy, but may also have other consequences.More...
The activation of T cells requires a co-stimulatory signal w......
The activation of T cells requires a co-stimulatory signal with T cell receptor activation, provided in many cases by activation of CD28 in resting T cells. 4-1BB (CD137) is a member of the TNF receptor gene family that provides another T cell co-stimulatory signal. 4-1BB is expressed by activated cytotoxic and helper T cells and its expression is induced by a variety of T cell stimuli, including activation of the T cell receptor or stimulation with mitogens. The ligand for 4-1BB (4-1BBL) is induced on activated antigen-presenting cells including macrophages, activating T cells expressing 4-1BB. Mice lacking 4-1BB survive and have an altered though functional immune response. T cells of mice lacking 4-1BB proliferate more rapidly than normal T cells, but have reduced cytokine secretion. The costimulatory signal provided by 4-1BB may act in combination with CD28 activation to prolong the T cell response, and may also act independently of CD28. Stimulation of T cells with the 4-1BB ligand may provide a therapeutic immune response in the treatment of cancer or viral infection. 4-1BB in T cells activates several signaling pathways. Like other members of the TNF receptor family, the 4-1BB receptor does not have an intrinsic kinase activity. TRAF2 is a signaling adapter that mediates signaling by other members of the TNF receptor family and that also binds to the cytoplasmic domain of ligand activated 4-1BB to activate intracellular kinase cascades. TRAF1 also binds to the cytoplasmic domain of 4-1BB although with lower affinity than TRAF2. One downstream effector activated by 4-1BB through TRAF2 is the transcription factor NF-kB. 4-1BB also activates map kinase pathways, including p38 and JNK activation. ASK1 dependent pathways can activate both p38 and JNK, and dominant negative ASK1 blocks their activation. Other kinase pathways may also be involved in 4-1BB activation of p38 and JNK, such as activation of germinal center kinase (GCK) or related kinases involved in activation of JNK and p38 by TNF. Map kinase activation along with NF-kB activation results in transcriptional activation of cytokine genes involved in T cell activation and signaling. The co-stimulatory signaling provided by 4-1BB shares some features with CD28 signaling, providing an explanation for the ability of 4-1BB to replace the CD28 costimulatory signal in some settings.More...
Interleukin 2 (IL-2) is a potent cytokine that can lead to c......
Interleukin 2 (IL-2) is a potent cytokine that can lead to cellular activation and proliferation. IL-2 Receptors are found on activated B-Cells, LPS treated Monocytes, and many T cells. The receptor is formed from three chains alpha (CD25), beta (CD122), and gamma (CD132). Primary signaling is through the JAK/Stat pathway and MAPKs.More...
IL12 and Stat4 Dependent Signaling Pathway in Th1 Development
Interleukin-12 (IL-12) promotes cell-mediated immunity by in......
Interleukin-12 (IL-12) promotes cell-mediated immunity by inducing Th1 cell differentiation and activation of both T cells and NK cells. Dendritic cells and macrophages in peripheral tissues act as antigen presenting cells and secrete IL-12 as one component of the antigen response, Th1 differentiation. The role of IL-12 in cellular immunity is largely mediated by the STAT-4 transcription factor. STAT-4 is essential for IL-12 activity and the phenotype of mice lacking STAT-4 is very similar to the phenotype of mice lacking the IL-12 receptor or IL-12. The role of IL-12 in Th1 differentiation may not be to induce the Th1 cell fate, but to stimulate growth of cells determined for the Th1 cell fate by the T-bet transcription factor. Several signaling pathways contribute to IL-12 activation of STAT-4 to regulate cell-mediated immune responses. The JAK kinases such as JAK2 and TYK2 interact with the activated IL-12 receptor and tyrosine phosphorylate the IL-12 receptor and STAT-4. IL-12 also activates a map kinase pathway activating the map kinase kinase MKK6 and p38. Phosphorylation of STAT-4 on serine 721 by p38 contributes to the full transcriptional activation of genes by STAT-4. Some of the events downstream of IL-12 appear to include genes activated indirectly by STAT-4, such as genes activated by the transcription factor ERM. ERM is in the Ets family of transcription factors, is activated by IL-12 and activates IL-12 inducible genes such as Interferon-gamma that are not activated by STAT-4 itself. Interferon-gamma transcription in T cells is also activated by other signals such as from the T cell receptor. Other proteins activated transcriptionally downstream of IL-12 and STAT-4 include the chemokine receptor CCR5 and IL-18 and its receptor. Some viruses, including HIV, repress cell-mediated immunity by blocking IL-12 signaling.More...
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...
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 makeupMore...
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...
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...
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...
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...
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...
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...
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...
JUN related interactors from protein-protein interaction data in HPRD (count: 116)
Basic Information
Positive relationships between JUN and other components at different levels (count: 0)
