GPLS genes significantly dysregulated in anterior cingulate ......
GPLS genes significantly dysregulated in anterior cingulate cortex by microarrayMore...
Positive relationships between PRKCB and other components at different levels (count: 0)
Positive relationship network of PRKCB in MK4MDD
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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 PRKCB and MDD (count: 0)
Negative relationships between PRKCB 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...
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...
Epithelial tight junctions (TJs) are composed of at least th......
Epithelial tight junctions (TJs) are composed of at least three types of transmembrane protein -occludin, claudin and junctional adhesion molecules (JAMs)- and a cytoplasmic 'plaque' consisting of many different proteins that form large complexes. The transmembrane proteins mediate cell adhesion and are thought to constitute the intramembrane and paracellular diffusion barriers. The cytoplasmic 'plaque' contains three major multi-protein complexes consisting largely of scaffolding proteins, the ZO protein complex, the CRB3-Pals1-PATJ complex and the PAR-3-aPKC-PAR-6 complex. The ZO protein complex appears to organize the transmembrane proteins and couple them to other cytoplasmic proteins and to actin microfilaments. Two evolutionarily conserved protein complexes, the CRB3 and PAR complexes are involved in the establishment and maintenance of epithelial cell polarity. Besides these three protein complexes which seem to be constitutively associated at TJs, a number of proteins with different functions has been identified at TJs. These include additional scaffolding proteins like MUPP1 and MAGI-1, adaptor proteins, transcription regulators and RNA processing factors, regulatory proteins like small GTPases and G-proteins, kinases and phosphatases, and heat shock proteins. These are proposed to be involved in junction assembly, barrier regulation, gene transcription, and perhaps other, presently undefined pathways.More...
Cerebellar long-term depression (LTD), thought to be a molec......
Cerebellar long-term depression (LTD), thought to be a molecular and cellular basis for cerebellar learning, is a process involving a decrease in the synaptic strength between parallel fiber (PF) and Purkinje cells (PCs) induced by the conjunctive activation of PFs and climbing fiber (CF). Multiple signal transduction pathways have been shown to be involved in this process. Activation of PFs terminating on spines in dendritic branchlets leads to glutamate release and activation of both AMPA and mGluRs. Activation of CFs, which make multiple synaptic contacts on proximal dendrites, also via AMPA receptors, opens voltage-gated calcium channels (VGCCs) and causes a generalized influx of calcium. These cellular signals, generated from two different synaptic origins, trigger a cascade of events culminating in a phosphorylation-dependent, long-term reduction in AMPA receptor sensitivity at the PF-PC synapse. This may take place either through receptor internalization and/or through receptor desensitization.More...
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...
Sodium transport across the tight epithelia of Na+ reabsorbi......
Sodium transport across the tight epithelia of Na+ reabsorbing tissues such as the distal part of the kidney nephron and colon is the major factor determining total-body Na+ levels, and thus, long-term blood pressure. Aldosterone plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct cells localized in the distal nephron, promoting sodium resorption and potassium excretion. Aldosterone enters a target cell and binds MR, which translocates into the nucleus and regulates gene transcription. Activation of MR leads to increased expression of Sgk-1, which phosphorylates Nedd4-2, an ubiquitin-ligase which targets ENAC to proteosomal degradation. Phosphorylated Nedd4-2 dissociates from ENAC, increasing its apical membrane abundance. Activation of MR also leads to increased expression of Na+/K+-ATPase, thus causing a net increase in sodium uptake from the renal filtrate. The specificity of MR for aldosterone is provided by 11beta-HSD2 by the rapid conversion of cortisol to cortisone in renal cortical collecting duct cells. Recently, besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented.More...
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...
Inflammatory immune response requires the recruitment of leu......
Inflammatory immune response requires the recruitment of leukocytes to the site of inflammation upon foreign insult. Chemokines are small chemoattractant peptides that provide directional cues for the cell trafficking and thus are vital for protective host response. In addition, chemokines regulate plethora of biological processes of hematopoietic cells to lead cellular activation, differentiation and survival. The chemokine signal is transduced by chemokine receptors (G-protein coupled receptors) expressed on the immune cells. After receptor activation, the alpha- and beta-gamma-subunits of G protein dissociate to activate diverse downstream pathways resulting in cellular polarization and actin reorganization. Various members of small GTPases are involved in this process. Induction of nitric oxide and production of reactive oxygen species are as well regulated by chemokine signal via calcium mobilization and diacylglycerol production.More...
Non-small-cell lung cancer (NSCLC) accounts for approximatel......
Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS and c-erbB-2, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Overexpression of c-erbB-2 or EGFR leads to a proliferative advantage. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector.Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect.More...
Natural killer (NK) cells are lymphocytes of the innate immu......
Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit MHC class I exprssion or alter its conformation. The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an adaptive immune response; cytotoxic granules are released onto the surface of the bound target cell, and the effector proteins they contain penetrate the cell membrane and induce programmed cell death.More...
Gap junctions contain intercellular channels that allow dire......
Gap junctions contain intercellular channels that allow direct communication between the cytosolic compartments of adjacent cells. Each gap junction channel is formed by docking of two 'hemichannels', each containing six connexins, contributed by each neighboring cell. These channels permit the direct transfer of small molecules including ions, amino acids, nucleotides, second messengers and other metabolites between adjacent cells. Gap junctional communication is essential for many physiological events, including embryonic development, electrical coupling, metabolic transport, apoptosis, and tissue homeostasis. Communication through Gap Junction is sensitive to a variety of stimuli, including changes in the level of intracellular Ca2+, pH, transjunctional applied voltage and phosphorylation/dephosphorylation processes. This figure represents the possible activation routes of different protein kinases involved in Cx43 and Cx36 phosphorylation.More...
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...
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...
There is now much evidence that VEGFR-2 is the major mediato......
There is now much evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells and it is considered to be a crucial signal transducer in both physiologic and pathologic angiogenesis. The binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the binding of VEGF to VEGFR-2 leads to dimerization of the receptor, followed by intracellular activation of the PLCgamma;PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway and subsequent initiation of DNA synthesis and cell growth, whereas activation of the phosphatidylinositol 3' -kinase (PI3K)-Akt pathway leads to increased endothelial-cell survival. Activation of PI3K, FAK, and p38 MAPK is implicated in cell migration signaling.More...
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...
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...
Leukocyte migaration from the blood into tissues is vital fo......
Leukocyte migaration from the blood into tissues is vital for immune surveillance and inflammation. During this diapedesis of leukocytes, the leukocytes bind to endothelial cell adhesion molecules (CAM) and then migrate across the vascular endothelium. A leukocyte adherent to CAMs on the endothelial cells moves forward by leading-edge protrusion and retraction of its tail. In this process, alphaL /beta2 integrin activates through Vav1, RhoA, which subsequently activates the kinase p160ROCK. ROCK activation leads to MLC phosphorylation, resulting in retraction of the actin cytoskeleton. Moreover, Leukocytes activate endothelial cell signals that stimulate endothelial cell retraction during localized dissociation of the endothelial cell junctions. ICAM-1-mediated signals activate an endothelial cell calcium flux and PKC, which are required for ICAM-1 dependent leukocyte migration. VCAM-1 is involved in the opening of the endothelial passage through which leukocytes can extravasate. In this regard, VCAM-1 ligation induces NADPH oxidase activation and the production of reactive oxygen species (ROS) in a Rac-mediated manner, with subsequent activation of matrix metallopoteinases and loss of VE-cadherin-mediated adhesion.More...
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...
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...
Fc epsilon RI-mediated signaling pathways in mast cells are ......
Fc epsilon RI-mediated signaling pathways in mast cells are initiated by the interaction of antigen (Ag) with IgE bound to the extracellular domain of the alpha chain of Fc epsilon RI. The activation pathways are regulated both positively and negatively by the interactions of numerous signaling molecules. Mast cells that are thus activated release preformed granules which contain biogenic amines (especially histamines) and proteoglycans (especially heparin). The activation of phospholipase A2 causes the release of membrane lipids followed by development of lipid mediators such as leukotrienes (LTC4, LTD4 and LTE4) and prostaglandins (especially PDG2). There is also secretion of cytokines, the most important of which are TNF-alpha, IL-4 and IL-5. These mediators and cytokines contribute to inflammatory responses.More...
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...
Cholera toxin (CTX) is one of the main virulence factors of ......
Cholera toxin (CTX) is one of the main virulence factors of Vibrio cholerae. Once secreted, CTX B-chain (CTXB) binds to ganglioside GM1 on the surface of the host's cells. After binding takes place, the entire CTX complex is carried from plasma membrane (PM) to endoplasmic reticulum (ER). In the ER, the A-chain (CTXA) is recognized by protein disulfide isomerase (PDI), unfolded, and delivered to the membrane where the membrane-associated ER-oxidase, Ero1, oxidizes PDI to release the CTXA into the protein-conducting channel, Sec61. CTXA is then retro-translocated to the cytosol and induces water and electrolyte secretion by increasing cAMP levels via adenylate cyclase (AC) to exert toxicity. Other than CTX, Vibrio cholerae generates several toxins that are perilous to eukaryotic cells. Zonula occludens toxin (ZOT) causes tight junction disruption through protein kinase C-dependent actin polymerization. RTX toxin (RtxA) causes actin depolymerization by covalently cross-linking actin monomers into dimers, trimers, and higher multimers. Vibrio cholerae cytolysin (VCC) is an important pore-forming toxin. The assembly of VCC anion channels in cells cause vacuolization and lysis.More...
Phagocytosis plays an essential role in host-defense mechani......
Phagocytosis plays an essential role in host-defense mechanisms through the uptake and destruction of infectious pathogens. Specialized cell types including macrophages, neutrophils, and monocytes take part in this process in higher organisms. After opsonization with antibodies (IgG), foreign extracellular materials are recognized by Fc gamma receptors. Cross-linking of Fc gamma receptors initiates a variety of signals mediated by tyrosine phosphorylation of multiple proteins, which lead through the actin cytoskeleton rearrangements and membrane remodeling to the formation of phagosomes. Nascent phagosomes undergo a process of maturation that involves fusion with lysosomes. The acquisition of lysosomal proteases and release of reactive oxygen species are crucial for digestion of engulfed materials in phagosomes.More...
PKC-catalyzed phosphorylation of inhibitory phosphoprotein of myosin phosphatase
The phosphorylation of myosin affects its role in smooth mus......
The phosphorylation of myosin affects its role in smooth muscle contraction, platelet formation and possibly other processes. Phosphorylation by myosin light chain kinase (MLCK) increases myosin activity and dephosphorylation by myosin phosphatase decreases myosin activity. CPI, a factor that binds to and inhibits myosin phosphatase, is a target of phosphorylation by PKC and PKN. The inhibitory activity of CPI is regulated by its own phosphorylation state; when CPI is phosphorylated, its inhibitory activity is increased. The activation of signal transduction cascades such as GPCR pathways can lead to activation of PKC, phosphorylation of CPI, inhibition of myosin phosphatase, increased myosin phosphorylation and increased smooth muscle contraction or platelet release. The action of histamine in vasoconstriction, for example, may be mediated by activation of PKC through the histamine receptor, resulting in phosphorylation of CPI-17, increased inhibition of myosin phosphatase, and increased smooth muscle contraction.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...
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...
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...
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...
CXCR4 is a chemokine receptor in the GPCR gene family, and i......
CXCR4 is a chemokine receptor in the GPCR gene family, and is expressed by cells in the immune system and the central nervous system. In response to binding its ligand SDF-1 (stromal cell-derived factor-1), CXCR4 triggers the migration and recruitment of immune cells. This ligand-receptor pair may also play a role in development of the nervous system. In addition to acting as a chemokine receptor, CXCR4 is a co-receptor for entry of HIV into T cells and ligands of CXCR4, including SDF-1 may help to block HIV infection. Early in the infection of an individual, HIV viruses often are tropic for the CCR5 coreceptor that provides for macrophage entry, then later in infection are tropic for CXCR4 and T cell entry. Viruses that are tropic for CXCR4 are generally syncitium forming, causing T cells to aggregate and be destroyed at a rapid rate. CXCR4 induces downstream signaling by several different pathways. As a GPCR, CXCR4 binding of SDF-1 activates G-protein mediated signaling, including downstream pathways such as ras, and PI3 kinase. PI3 kinase activated by SDF-1 and CXCR4 plays a role in lymphocyte chemotaxis in response to these signals. One endpoint of CXCR4 signaling is the activation of transcription factors such as AP-1 and chemokine regulated genes. JAK/STAT signaling pathways also appear to play a role in SDF-1/CXCR4 signaling. Delineation of the signaling mechanisms utilized by CXCR4 may assist in determining the role of CXCR4 in HIV infection and in the immune response.More...
Growth hormone plays a major role in regulating growth durin......
Growth hormone plays a major role in regulating growth during childhood and adolescence and also regulates metabolism. Defects in growth hormone signaling can result in dwarfism and decreases in growth hormone levels with age have been suggested to play a role in the reduced function of some physiological systems. Growth hormone signals a response in cells through the growth hormone receptor, a member of the cytokine receptor gene family. Growth hormone causes the receptor to dimerize, activating the JAK2 protein kinase. The activity of JAK2 mediates many of the downstream responses to growth hormone through phosphorylation of STAT transcription factors, MAP kinases, other kinase cascades and molecules involved in metabolism like IRS-1. Factors like SOCS and SHP-1 appear to play a role in the down regulation of signaling by growth hormone and cytokines.More...
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...
Eosinophils are a key class of leukocytes involved in inflam......
Eosinophils are a key class of leukocytes involved in inflammatory responses, including allergic reactions in skin and airway. The eosinophil response in inflammation is absent in mice lacking CCR3, indicating the key role of this G protein coupled receptor in inflammation and allergic responses. Eotaxin is a chemokine ligand for CCR3 that recruits eosinophils to the site of inflammation and activates them. Other chemokine ligands of CCR3 include eotaxin-2, MCP-3, MCP-4, and RANTES. Multiple signaling pathways activated by CCR3 participate in the inflammatory response of eosinophils. Eotaxin stimulates intracellular calcium release, production of reactive oxygen species, and changes in actin polymerization through a pertussis sensitive pathway. Rho and ROCK regulate actin stress fiber formation and are required for eosinophil chemotaxis. Rho is a G protein that activates ROCK, a protein kinase. Map kinase pathways are also involved in chemotaxis. Another key action of activated eosinophils is the release of reactive oxygen species, causing tissue damage during chronic inflammatory responses. Blocking eosinophil activation and the signaling pathways that lead to chemotaxis, degranulation and reactive oxygen release may alleviate inflammatory conditions and inflammation-associated tissue damage.More...
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...
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...
Thrombin signaling and protease-activated receptors
Thrombin is an extracellular protease that is involved in th......
Thrombin is an extracellular protease that is involved in the clotting of blood and inflammation through its action on platelets and endothelial cells in the vasculature and that plays a role in thrombosis and myocardial infarction. The protease activated receptors PAR1 and PAR4 are cellular targets of thrombin signaling and members of the G-protein coupled receptor gene family. Both of these receptors are cleaved in their N-terminus by thrombin, unmasking a portion of the receptor sequence that acts itself as a tethered peptide ligand that activates the receptor. The tethered ligand that activates PAR1 is SFLLRN and the tethered ligand that activates PAR4 is GYPGQV. Other members of the family include PAR2 which is activated by trypsin rather than thrombin and PAR3 which seems to play a role in the activation of other PARs but does not itself transduce a signal directly. Addition of peptide agonist exogenously in solution can also activate PAR1, PAR2 and PAR4. PAR1 activation may be involved in the dilation of arteries during inflammation through the action of thrombin on endothelial cells and in platelet activation by thrombin during clotting. PAR1 and PAR2 activation cause bronchodilation in airway and may protect against asthma. PAR 4 activation by thrombin activates platelets during clotting and mice lacking PAR4 have impaired clotting and platelets that do not respond to thrombin signaling. The action of thrombin on PAR1 and PAR4 on platelets and endothelial cells may also contribute to vascular permeability and inflammation. Activated PARs appear to couple primarily through Gq-mediated stimulation of inositol phosphate metabolism and intracellular calcium levels to activate platelets. PAR1 and PAR4 also appear to couple to multiple G-proteins and transduce signals through more than one G-protein mediated pathway in some circumstances. Signaling by PAR1 and PAR4 through Galpha12 pathways couples to Rho signaling and changes in cytoskeletal structure and cell shape. Gi activation does not appear necessary for platelet activation by PAR1 or PAR4, and platelet activation by these receptors requires an ADP signal perhaps acting through the platelet-associated purinergic receptor P2Y12. Gi-coupled signaling may play a role in mitogenic PAR signaling in some settings through Map kinase activation. Activation of Rho by PAR1 can induce cellular transformation through a Galpha12 mediated mechanism and sustained rho-dependent phosphorylation of the myosin light chain by PAR1 contributes to cytoskeletal changes and activation of platelets. Since the activation of PARs by protease cleavage is irreversible the primary mechanism for down-regulation of the PAR signaling cascade appears to be internalization and degradation of PAR receptors.More...
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...
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...
Aspirin Blocks Signaling Pathway Involved in Platelet Activation
Activation of the protease-activated GPCRs in platelets cont......
Activation of the protease-activated GPCRs in platelets contributes to platelet activation in clotting. The protease-activated receptors PAR1 and PAR4 are cleaved by the protease thrombin, releasing a tethered peptide ligand that activates the receptor and triggers intracellular calcium release. Platelets from mice lacking the PAR4 gene are not activated by thrombin and are impaired in clotting, supporting the importance of thrombin signaling through PAR4 in clotting. Human platelets express both PAR1 and PAR4, with PAR1 playing a more dominant role in clotting in humans. Calcium release induced by PARs activates PKC, modulating integrin alpha IIB beta 3 (glycoprotein IIb/IIIa) and opening integrin ligand binding sites to contribute to platelet aggregation. Intracellular calcium increases induced by thrombin activates phospholipase A2, liberating arachidonic acid, the first step in prostaglandin and thromboxane biosynthesis. Ras/Map kinase activation by the PAR receptors also activates phospholipase A2. The activation of PAR-induced platelet aggregation is inhibited by aspirin, indicating that thromboxane production induced by PAR signaling contributes to platelet activation. Arachidonic acid is converted to the prostaglandin PGG2 by the enzyme Cox-1 in platelets, and Cox-1 is inhibited by aspirin, reducing thromboxane A2 production by platelets. Thromboxane is a potent vasoconstrictor and platelet activator, so inhibition of Cox-1 in platelets by aspirin may explain some of the cardioprotective actions of aspirin.More...
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...
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...
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...
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...
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...
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...
eIF-4F and p70 S6 kinase play critical roles in translationa......
eIF-4F and p70 S6 kinase play critical roles in translational regulation. eIF-4F is a complex whose functions include the recognition of the mRNA 5' cap structure (eIF-4E), delivery of an RNA helicase to the 5' region (eIF-4A), bridging of the mRNA and the ribosome (eIF-4G), and circularization of the mRNA via interaction between eIF-4G and the poly(A) binding protein (PABP). Several stimuli, including growth factors and cytokines, regulate the eIF-4 complex and p70 S6 kinase by initiating a phosphorylation cascade involving the sequential activation of PI3-K, PDK1/2, Akt/PKB, and FRAP/mTOR kinase. FRAP/mTOR, together with an unidentified kinase, phosphorylates 4E-BP, leading to its dissociation from and activation of eIF-4E. MNK1/2, activated by ERK and p38 MAPK, phosphorylates and activates eIF-4E. Both processes contribute to the association of eIF-4E and eIF-4G to form the active eIF-4F complex, a necessary component of the 48S initiation complex. Phosphorylation of ribosomal protein S6 by p70 S6 kinase stimulates the translation of mRNAs with a 5' oligopyrimidine tract which typically encode components of the protein synthesis.More...
Sphingosine-1-phosphate (S1P) is an example of lipid messeng......
Sphingosine-1-phosphate (S1P) is an example of lipid messengers with both intracellular and extracellular functions. Intracellularly S1P regulates proliferation and survival; extracellularly S1P is a ligand for EDG1 (also known as S1P1). Activation of sphingosine kinase (SPHK), the enzyme that catalyzes the phosphorylation of sphingosine, increases cellular levels of S1P. Inhibitors of SPHK block formation of S1P and inhibit cellular proliferation induced by a variety of factors, including as an example platelet-derived growth factor (PDGF) and PMA. In a study using endothelial cells it was demonstrated that S1P induces activation of alpha-v and B3 integrins via RhoA. S1P also activates Akt via Gi and PI3K. The activated Akt phosphorlyates the Edg1 receptor on threonine 236 leading to the activation of Rac1 and subsequent signals leading to actin assembly, chemotaxis and lamellipodia formation. Edg1 stimulation also leads to the activation of the ERK signaling cascade resulting in anti-apoptotic reversal, proliferation and cell survival.More...
Nerve growth factor (NGF) is a neurotrophic factor that stim......
Nerve growth factor (NGF) is a neurotrophic factor that stimulates neuronal survival and growth through TrkA, a member of the trk family of tyrosine kinase receptors that also includes TrkB and TrkC. Some NGF responses are also mediated or modified by p75LNTR, a low affinity neurotrophin receptor. Binding of NGF to TrkA stimulates neuronal survival, and also proliferation. Pathways coupled to these responses are linked to TrkA through association of signaling factors with specific amino acids in the TrkA cytoplasmic domain. Cell survival through inhibition of apoptosis is signaled through activation of PI3-kinase and AKT. Ras-mediated signaling and phospholipase C both activate the MAP kinase pathway to stimulate proliferation.More...
The cellular activation of the caspase cascade resulting in ......
The cellular activation of the caspase cascade resulting in cell death is triggered by chemical damage to DNA which stimulates a sequence resulting in the cleavage of Bid in a manner similar to the binding of so called death-receptors or directly initiates the permeability transition of the mitochondrial membrane. The permiability transition releases several factors including cytochrome c, AIF and other factors in to the cytoplasm. Cytochrome c, a key protein in electron transport, is released from mitochondria in response to apoptotic signals, and activates Apaf-1, a protease released from mitochondria. Activated Apaf-1 activates caspase-9 and the rest of the caspase cascade. The caspases are a class of cysteine proteases that includes several representatives involved in apoptosis. The caspases convey the apoptotic signal in a proteolytic cascade, with caspases cleaving and activating other caspases that then degrade other cellular targets that lead to cell death.More...
Activation of Src by Protein-tyrosine phosphatase alpha
Progression through the cell cycle is accompanied by activat......
Progression through the cell cycle is accompanied by activation of the proto-oncogene c-Src, a protein tyrosine kinase. Overexpression of Src leads to tyrosine phosphorylation of multiple protein substrates and cellular transformation. During interphase the Src protein folds back upon itself to stay in the inactive state, with a phophotyrosine residue in one domain at Tyrosine 529 bound by an SH2 domain in the same protein. Activation of c-Src involves protein-tyrosine phosphatase alpha (PTP-alpha, or RPTP-alpha), a transmembrane protein with a cytoplasmic phosphatase domain. A variety of evidence has indicated that PTP-alpha dephosphorylates c-Src at Tyr529, allowing Src to open up and become activated, and that this activation occurs in association with mitosis. To activate Src, PTP-alpha must first open up the folded Src through binding itself to the phosphorylated Src domain, a process blocked by binding of Grb-2 to PTP-alpha at phosphorylated Tyr789. PTP-alpha phosphorylated at Tyr789 also binds to the Src SH2 domain, causing the Src structure to open at Src Tyr529 to become available for dephosphorylation. During mitosis the mitotic kinase Cdc-2 phosphorylates Src, along with other cellular substrates, and in so doing makes Src more prone PTP-alpha dephosphorylation and activation. The activity of PTP-alpha toward Src is also regulated by phosphorylation of PTP-alpha by protein kinase C at serines 180 and 204, releasing the inhibition of PTP-alpha by Grb-2. In the normal cell cycle, Src activity is down-regulated after cell division through dephosphorylation by protein phosphatases and phosphorylation by Csk (C-terminal src kinase) and PTP-alpha dephoshorylation returns the cycle to its interphase condition. The regulation of Src activity during mitosis demonstrates how protein phosphorylation can shifts the delicate equilibrium of molecular interactions and cellular responses.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...
The G-protein coupled receptor (GPCR) family transduces extr......
The G-protein coupled receptor (GPCR) family transduces extracellular signals across the plasma membrane, activating cellular responses through a variety of second messenger cascades. These receptors provide rapid responses to a variety of stimuli, and are often rapidly attenuated in their signaling. Failure to attenuate GPCR signaling can have dramatic consequences. One method to attenuate GPCR signaling is by removal of the stimulus from the extracellular fluid. At the synapse, removal of neurotransmitter or peptide signaling molecules is accomplished by either reuptake or degradation. Acetylcholine is removed from synapses through degradation by the enzyme acetylcholinesterase. Inhibition of acetylcholinesterase results in prolonged signaling at the neuromuscular junction, and uncontrollable spasms in humans caused by nerve gas or in insects by some insecticides. Inhibition of acetylcholinesterase is also used therapeutically to treat Alzheimer's disease, compensating for the loss of cholinergic neurons. Transporters for serotonin, dopamine, GABA and noradrenaline remove these neurotransmitters from the synapse to terminate signaling. Antidepressants such as Prozac inhibit reuptake of serotonin and many drugs of abuse such as cocaine act by blocking reuptake of dopamine or adrenaline. Reuptake not only terminates signaling, but can also conserve neurotransmitter through recycling back into the presynaptic cell. The next step in the attenuation of GPCR signaling is receptor desensitization, in which receptors are modified to no longer transduce a signal even if the stimulus is still present. Desensitization of GPCRs occurs through protein kinases that phosphorylate the GPCR to turn off signaling. Downstream protein kinases such as PKA and PKC turned on by GPCR signaling can phosphorylate the activated GPCR and other GPCRs to prevent further signaling. G-protein receptor kinases (GRKs) are a family of kinases that specifically phosphorylate only agonist-occupied GPCRs. GRKs attenuate GPCR signaling in concert with arrestins, proteins that bind GRK-phosphorylated GPCRs to disrupt interaction with G-protein and to terminate signaling. Reducing the number of receptor expressed on the cell surface can also attenuate receptor signaling. Many GPCRs are removed from the cell surface by receptor-mediated endocytosis when they are activated. Endocytosis of activated GPCRs appears to be stimulated by GRKs and arrestins. Once internalized, receptors can either be degraded in lysosomes or they can be recycled back to the cell surface.More...
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...
Transcription factor CREB and its extracellular signals
The transcription factor CREB binds the cyclic AMP response ......
The transcription factor CREB binds the cyclic AMP response element (CRE) and activates transcription in response to a variety of extracellular signals including neurotransmitters, hormones, membrane depolarization, and growth and neurotrophic factors. Protein kinase A and the calmodulin-dependent protein kinases CaMKII stimulate CREB phosphorylation at Ser133, a key regulatory site controlling transcriptional activity. Growth and neurotrophic factors also stimulate CREB phosphorylation at Ser133. Phosphorylation occurs at Ser133 via p44/42 MAP Kinase and p90RSK and also via p38 MAP Kinase and MSK1. CREB exhibit deficiencies in spatial learning tasks, while flies overexpressing or lacking CREB show enhanced or diminished learning, respectively.More...
CBL mediated ligand-induced downregulation of EGF receptors
As with many cell-surface receptors, activation of the EGF r......
As with many cell-surface receptors, activation of the EGF receptor can result in receptor internalization through receptor-mediated endocytosis, desensitizing further receptor signaling. This process requires clathrin and occurs in clathrin-coated pits, which pinch off from the plasma membrane to form vesicles that move to the early endosome. From the early endosome, receptors can either be recycled back to the cell surface, or they can move through the late endosome to the lysosome for proteolytic degradation. The sorting of receptors in the early endosome for degradation requires the tyrosine kinase activity of activated growth factor receptor, and involves ubiquitination of the receptor. Targeting of receptors for degradation requires members of the Cbl gene family. Cbl proteins bind to tyrosine phosphorylated EGF receptor, and are E3 ubiquitination ligases that label receptor for degradation. Cbl also recruits Cin85 to the receptor complex, and blocking Cin85 interaction blocks receptor internalization and degradation. Endophilins are also a member of this receptor-bound protein complex. In its role as a ubiquitin ligase and docking protein, Cbl desensitizes EGF signaling and also opposes cellular proliferation induced by EGF. EGF activation also appears to activate the tyrosine kinase Src, which phosphorylates Cbl, and helps to activate the ubiquitination and degradation of EGF receptor. PKC activation and threonine phosphorylation of the EGF receptor can induce heterologous receptor internalization, but opposes Cbl-mediated receptor degradation. PKC phosphorylated receptors are sorted for recycling to the cell surface, and directed away from the late endosome and proteosome. Other growth factor receptors are regulated in a similar manner, including the PDGF receptor, HGF receptor and the CSF-1 receptor, indicating that this is a fairly general regulatory mechanism. The importance of Cbl in the down-regulation of growth factor signaling means that it will have an important role in cellular transformation and the development and treatment of cancer.More...
Vascular endothelial growth factor (VEGF) plays a key role i......
Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis such as tumor growth and ischemic diseases. Hypoxia is a potent inducer of VEGF in vitro. The increase in secreted biologically active VEGF protein from cells exposed to hypoxia is partly because of an increased transcription rate, mediated by binding of hypoxia-inducible factor-1 (HIF1) to a hypoxia responsive element in the 5'-flanking region of the VEGF gene. bHLH-PAS transcription factor that interacts with the Ah receptor nuclear translocator (Arnt), and its predicted amino acid sequence exhibits significant similarity to the hypoxia-inducible factor 1alpha (HIF1a) product. HLF mRNA expression is closely correlated with that of VEGF mRNA.. The high expression level of HLF mRNA in the O2 delivery system of developing embryos and adult organs suggests that in a normoxic state, HLF regulates gene expression of VEGF, various glycolytic enzymes, and others driven by the HRE sequence, and may be involved in development of blood vessels and the tubular system of lung. VEGF expression is dramatically induced by hypoxia due in large part to an increase in the stability of its mRNA. HuR binds with high affinity and specificity to the VRS element that regulates VEGF mRNA stability by hypoxia. In addition, an internal ribosome entry site (IRES) ensures efficient translation of VEGF mRNA even under hypoxia. The VHL tumor suppressor (von Hippel-Lindau) regulates also VEGF expression at a post-transcriptional level. The secreted VEGF is a major angiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. Cellular and circulating levels of VEGF are elevated in hematologic malignancies and are adversely associated with prognosis. Angiogenesis is a very complex, tightly regulated, multistep process, the targeting of which may well prove useful in the creation of novel therapeutic agents. Current approaches being investigated include the inhibition of angiogenesis stimulants (e.g., VEGF), or their receptors, blockade of endothelial cell activation, inhibition of matrix metalloproteinases, and inhibition of tumor vasculature. Preclinical, phase I, and phase II studies of both monoclonal antibodies to VEGF and blockers of the VEGF receptor tyrosine kinase pathway indicate that these agents are safe and offer potential clinical utility in patients with hematologic malignancies.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...
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...
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...
Repetitive presynaptic activity causes long lasting changes ......
Repetitive presynaptic activity causes long lasting changes in the postsynaptic transmission by changing the type and the number of AMPA receptors. These changes are brought about by trafficking mechanisms that are mainly controlled by activity dependent phosphorylation/desphosphorylation of the GluR1/GluR2 subunits.More...
Trafficking of GluR2-containing receptors is governed by pro......
Trafficking of GluR2-containing receptors is governed by protein protein interactions that are regulated by phosphorylation events. GluR2 binds NSF and AP2 in the proximal C terminal region and binds PICK and GRIP1/2 in the extreme C terminal region. GluR2 interaction with NSF is necessary to maintain the synaptic levels of GluR2-containing AMPA receptors both at basal levels and under conditions of synaptic activity. GluR2 interaction with GRIP helps anchor AMPA receptors at the synapse. Phosphorylation of GluR2 at S880 disrupts GRIP interaction but allows binding of PICK. PICK is activated by Ca sensitive Protein kinase C :768-75)More...
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...
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...
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...
PRKCB related interactors from protein-protein interaction data in HPRD (count: 68)
Basic Information
Positive relationships between PRKCB and other components at different levels (count: 0)
