Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptors for chemoattractants that direct the migration of phagocytic leukocytes to sites of injury/infection also modulate many other leukocyte functions that are critical to the inflammatory response. These chemoattractant receptors, members of the G protein-coupled heptahelical receptor family, have been classically linked to cell activation via phospholipase C, calcium, and protein kinase C. We show here that activation of the N-formyl peptide chemoattractant receptor stimulates an additional protein kinase C-independent pathway through the Src-related tyrosine kinase, Lyn, in human neutrophils. We demonstrate that activation of Lyn is associated with binding to the Shc adapter protein, which becomes phosphorylated on tyrosine residues. This interaction appears to be mediated via the Shc SH2 domain. Complexes of phosphorylated Lyn and Shc with phosphatidylinositol 3-kinase are rapidly formed in stimulated neutrophils, correlating with phosphatidylinositol 3,4,5-trisphosphate [corrected] formation and cell activation. This signaling pathway involving a Src-related kinase and the Shc adapter protein provides a potential mechanism linking chemoattractant receptors to downstream events involving Rac activation and NADPH oxidase. Regulation of Shc by G protein-coupled receptors may also allow these receptors to modulate the activity of the Ras/mitogen-activated protein kinase cascade.
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PMID:G protein-coupled chemoattractant receptors regulate Lyn tyrosine kinase.Shc adapter protein signaling complexes. 765 13

Thrombopoietin has an essential role in megakaryopoiesis and thrombopoiesis. To investigate the signaling processes induced by thrombopoietin, we have employed human platelets and recently demonstrated that thrombopoietin induces rapid tyrosine phosphorylation of Jak-2, Tyk2, Shc, Stat3, Stat5, p120(c-cbl) and other proteins in human platelets. Because the apparent molecular weight of a major tyrosine phosphorylated protein in platelets stimulated by thrombopoietin is approximately 85 to 95 kD, we examined the possibility that this could be Vav, a 95-kD proto-oncogene product. Specific antisera against Vav recognized the same 95 kD protein in lysates of Jurkat cells, which are known to express Vav, and platelets, indicating that platelets have Vav. Thrombopoietin induced rapid tyrosine phosphorylation of Vav in platelets without an elevation in cytosolic free calcium concentration or activation of protein kinase C. Vav was also tyrosine phosphorylated upon treatment of platelets with thrombin, collagen, or U46619, which activate phospholipase C, leading to an increased ionized calcium concentration and activation of protein kinase C. Ionomycin or phorbol 12-myristate 13-acetate (PMA) also induces tyrosine phosphorylation of Vav, suggesting that an increase in ionized calcium concentration or activation of protein kinase C may lead to phosphorylation of Vav. Thrombopoietin also induced tyrosine phosphorylation of Vav in FDCP-2 cells, genetically engineered to express human c-Mpl (FDCP-hMpl5). However, neither ionomycin nor PMA induced an increase in tyrosine phosphorylation of Vav in FDCP-hMpl5 cells, suggesting that the calcium and protein kinase C pathways of Vav phosphorylation may be unique to platelets. Further, Vav became incorporated into the Triton X-100 insoluble 10,000 g sedimentable residue in an aggregation-dependent manner, suggesting that it may have a regulatory role in platelet cytoskeletal processes. Vav was constitutively associated with a 28-kD adapter protein, Grb2, which is also incorporated into the cytoskeleton in an aggregation-dependent fashion. Lastly, we found that Vav is cleaved when there is activation of calpain, a protease that may have a role in postaggregation signaling processes. Our data suggest that thrombopoietin and other agonists may induce tyrosine phosphorylation of Vav by different mechanisms and Vav may also be involved in signaling during platelet aggregation by its redistribution to the cytoskeleton.
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PMID:Thrombopoietin and thrombin induce tyrosine phosphorylation of Vav in human blood platelets. 910 97

Growth hormone (GH) has long been recognized as one of the principal factors that control postnatal growth. Advances made in the last 5 years have increased our understanding of the intracellular signaling mechanisms subsequent to GH binding. The earliest event in GH signaling appears to be the binding of a single GH molecule by a pair of GH receptors (GHRs). The dimerization of GHRs leads to the activation of Janus kinase 2 (JAK2), a nonreceptor tyrosine kinase that associates with the cytoplasmic domain of GHR. It is thought that all signaling downstream from GHR depends on this initial activation of JAK2. Once activated, JAK2 tyrosyl-phosphorylates both itself and the cytoplasmic domain of GHR. These phosphorylated tyrosine residues act as docking sites for various signaling molecules that contain Src homology 2 (SH-2) or other phosphotyrosyl-binding domains. The signaling molecules that are recruited and activated by the GHR-JAK2 complex include signal transducers and activators of transcription (Stat) factors, the adapter protein Shc, and the insulin receptor substrates (IRSs) 1 and 2. The recruitment and activation of these signaling intermediates leads to the activation of enzymes such as MAP kinase, phosphatidylinositol-3'-kinase, protein kinase C, and phospholipase A2 and to the release of various second messengers such as diacylglycerol, calcium, and nitric oxide. Ultimately, these pathways modulate cellular functions such as gene transcription, metabolite transport, and enzymatic activities that affect the GH-dependent control of growth and metabolism.
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PMID:Growth-hormone signal transduction. 925 27

Contraction of smooth muscle cells is generally assumed to require Ca2+/calmodulin-dependent phosphorylation of the 20-kDa myosin light chains. However, we report here that in the absence of extracellular calcium, phenylephrine induces a contraction of freshly isolated ferret aorta cells in the absence of increases in intracellular ionized calcium or light chain phosphorylation levels but in the presence of activation of mitogen-activated protein kinase. A protein at 36 kDa co-immunoprecipitated with the mitogen-activated protein kinase and was identified as the actin-binding protein, calponin, by immunoblot. An overlay assay further confirmed an interaction between the kinase and calponin, even though the kinase did not phosphorylate calponin in vitro. Calponin also co-immunoprecipitated from smooth muscle cells with protein kinase C-epsilon. High resolution digital confocal studies indicated that calponin redistributes to the cell membrane during phenylephrine stimulation at a time when mitogen-activated protein kinase and protein kinase C-epsilon are targeted to the plasmalemma. These results suggest a role for calponin as a signaling molecule, possibly an adapter protein, linking the targeting of mitogen-activated protein kinase and protein kinase C-epsilon to the surface membrane.
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PMID:Calponin and mitogen-activated protein kinase signaling in differentiated vascular smooth muscle. 931 27

G-protein-coupled receptors that mediate cellular responses to a variety of humoral, endothelial-, or platelet-derived substances are able to stimulate MAP kinase activity. In transfected model systems, G-protein-coupled receptors that couple to pertussis toxin-insensitive G proteins of the Gq/11 family mediate this activation predominantly via a PKC-dependent mechanism. In contrast, activation of MAP kinase by receptors that couple to pertussis toxin-sensitive Gi proteins is PKC-independent and requires downstream activation of the low-molecular-weight G protein, Ras. This pathway can be inhibited by coexpression of peptides that sequester Gbetagamma subunits, and is mimicked by overexpression of Gbetagamma subunits. This Ras-dependent MAP kinase activation requires tyrosine phosphorylation of "docking proteins," including the shc adapter protein, and depends upon recruitment of Grb2/Sos1 complexes to the plasma membrane, thus resembling the pathway of MAP kinase activation employed by the receptor tyrosine kinases. Other molecules, including PI-3-kinases and phosphotyrosine phosphatases, probably also contribute to Gbetagamma-subunit-mediated assembly of a mitogenic signaling complex. Identification of the G-protein-coupled, receptor-regulated tyrosine kinase(s), and the means by which the mitogenic signaling complex is assembled at the plasma membrane, remain subjects of further study.
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PMID:G-protein-coupled receptors and their regulation: activation of the MAP kinase signaling pathway by G-protein-coupled receptors. 934 57

The cytoplasmic regions of the receptors for epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) bind and activate phospholipase C-gamma1 (PLC-gamma1) and other signaling proteins in response to ligand binding outside the cell. Receptor binding by PLC-gamma1 is a function of its SH2 domains and is required for growth factor-induced cell cycle progression into the S phase. Microinjection into MDCK epithelial cells and NIH 3T3 fibroblasts of a polypeptide corresponding to the noncatalytic SH2-SH2-SH3 domains of PLC-gamma1 (PLC-gamma1 SH2-SH2-SH3) blocked growth factor-induced S-phase entry. Treatment of cells with diacylglycerol (DAG) or DAG and microinjected inositol-1,4,5-triphosphate (IP3), the products of activated PLC-gamma1, did not stimulate cellular DNA synthesis by themselves but did suppress the inhibitory effects of the PLC-gamma1 SH2-SH2-SH3 polypeptide but not the cell cycle block imposed by inhibition of the adapter protein Grb2 or p21 Ras. Two c-fos serum response element (SRE)-chloramphenicol acetyltransferase (CAT) reporter plasmids, a wild-type version, wtSRE-CAT, and a mutant, pm18, were used to investigate the function of PLC-gamma1 in EGF- and PDGF-induced mitogenesis. wtSRE-CAT responds to both protein kinase C (PKC)-dependent and -independent signals, while the mutant, pm18, responds only to PKC-independent signals. Microinjection of the dominant-negative PLC-gamma1 SH2-SH2-SH3 polypeptide greatly reduced the responses of wtSRE-CAT to EGF stimulation in MDCK cells and to PDGF stimulation in NIH 3T3 cells but had no effect on the responses of mutant pm18. These results indicate that in addition to Grb2-mediated activation of Ras, PLC-gamma1-mediated DAG production is required for EGF- and PDGF-induced S-phase entry and gene expression, possibly through activation of PKC.
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PMID:Requirement for phospholipase C-gamma1 enzymatic activity in growth factor-induced mitogenesis. 941 5

Eosinophils are potent effector cells contributing to allergic inflammation and asthma. The differentiation, recruitment, and effector functions of eosinophils are greatly affected by interleukin (IL)-5. In the eosinophil, signal transduction pathways including Jak-STAT and Ras-Raf-MAP kinase are stimulated by IL-5 and enzymatic activation of tyrosine kinases Jak-2 and Lyn has been demonstrated. The participation of adapter proteins in the responses of the Ras-Raf-MAP kinase pathway has been documented in many cytokine family receptors but the expression and activation of these proteins have not been demonstrated in eosinophils. In these studies, we have found three isoforms of the adapter protein, Shc, to be expressed in eosinophils. One of these isoforms, p52 Shc, was tyrosine phosphorylated following IL-5 treatment of eosinophils. A second adapter protein, Grb2, coimmunoprecipitated with Shc following IL-5 stimulation of eosinophils. Furthermore, p52 Shc was increasingly associated with a cell fraction resistant to detergent solubilization, following IL-5 administration. This cell fraction of limited detergent solubility is a complex mixture of proteins and the adapter protein Grb2, the tyrosine kinases Jak-2 and Lyn, the nucleotide exchange factor Vav, and the serine-threonine kinases p45 MAP kinase, Raf-1, and PKCbeta, were distributed either wholly or partially in the same fraction, as were the cytoskeletal proteins actin and vimentin. Only p52 Shc, however, demonstrated discernibly increased association with this fraction following IL-5 stimulation of eosinophils. These data suggest that IL-5 activates a signal transduction pathway utilizing the adapter proteins Shc and Grb2 in the human eosinophil.
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PMID:Interleukin 5 signals through Shc and Grb2 in human eosinophils. 944 48

Rat prostate-cancer-cell stable-transfectants expressing either antisense-fibroblast growth factor (FGF-1) or antisense-FGF-2 transcripts that respectively have either undetectable FGF-1 or profoundly diminished FGF-2 protein content, were used for analyses of FGF-2 and/or 12-O-tetradecanoylphorbol 12-acetate (TPA) modulation of cell proliferation. Antisense-FGF-2 transfectant doubling-time was 2.6-fold greater than that of vector-control transfectants. FGF-2 and TPA respectively caused 2.5- and 3.0-fold reductions in antisense-FGF-2 transfectant doubling-time. Culture of antisense-FGF-2 transfectants in medium containing both FGF-2 and TPA further reduced their doubling time; however, this effect was not statistically different from that achieved by TPA treatment alone. Antisense-FGF-1 transfectant doubling-time was 2.2-fold greater than that of vector-control transfectants and was reduced 2.0- or 2.3-fold, respectively, when these cells were cultured in medium containing FGF-2 or TPA. In contrast to the results for antisense-FGF-2 transfectants, culture of antisense-FGF-1 transfectants in medium containing both FGF-2 and TPA caused a 2.6-fold reduction in transfectant doubling-time that was significantly greater than that caused by independent treatment with either FGF-2 or TPA. FGF-2 promoted rapid activation of rat prostate-cancer-cell PKCalpha and PKCepsilon, as assessed by isozyme translocation from the soluble to particulate cell fraction, and only moderately altered PKCdelta distribution. By contrast, TPA promoted rapid activation of all three PKC isozymes. Both the TPA- and FGF-2-mediated PKC activation were prolonged and possibly involved cyclic redistribution of isozymes between soluble and particulate cell fractions. FGF-2 also caused rapid phosphorylation of prostate-cancer-cell Shc, the adapter protein that mediates FGF-receptor-modulated ras signaling. The results of these studies indicate that FGF-2 and TPA independently and conjointly modulate rat prostate-cancer-cell antisense-transfectant doubling time and suggest that effector modulation of rat prostate-cancer-cell proliferation is achieved by processes involving PKC and/or ras mediated signaling.
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PMID:Fibroblast growth factor-2 and TPA enhance prostate-cancer-cell proliferation and activate members of the Ras and PKC signal transduction pathways. 963 22

Growth factors and their receptors are known to play important roles in normal cell proliferation, tissue repair, and ulcer healing. Epidermal growth factor (EGF) inhibits acid secretion, protects gastric mucosa against injury, mediates mucosal adaptation, and accelerates gastroduodenal ulcer healing. EGF exerts its actions by binding to its receptor (EGF-R), which is a transmembrane protein tyrosine kinase. Binding of EGF to its receptor triggers receptor dimerization and autophosphorylation, recruitment of kinase substrates (signaling enzyme adapter proteins with an SH2 domain, Grb2 adapter protein, and Grb2-SOS complex). These events lead to Ras (GTP-binding protein) phosphorylation and activation of the Ras/Raf/MAP kinase pathway, in turn leading to phosphorylation of regulatory proteins and transcription factors and culminating in cell proliferation. Other pathways potentially activated by EGF include the phosphatidylinositol pathway (leading to activation of protein kinase C and an increase in cytosolic calcium) and the JAK/STAT signaling pathway. While EGF-induced signaling events have been extensively studied in various cell systems, predominantly neoplastic and/or transformed cells, the relevance of those findings to gastric mucosal injury repair or ulcer healing is as yet not fully elucidated. This paper is intended to provide an overview of signaling pathways triggered by EGF-R activation and on this background to summarize current knowledge pertaining to involvement of EGF-R signaling pathways in gastric mucosal repair and ulcer healing.
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PMID:Signal transduction cascades triggered by EGF receptor activation: relevance to gastric injury repair and ulcer healing. 975 21

p130(Cas) (Crk-associated substrate), because of its structure as an adapter protein, can interact when tyrosine-phosphorylated with a large number of cellular proteins and therefore be an important modulator of downstream signals. A number of growth factors, lipids, and a few G protein-coupled receptors can stimulate p130(Cas) tyrosine phosphorylation. Recent studies show that tyrosine phosohorylation of intracellular proteins by the hormone/neurotransmitter cholecystokinin (CCK) in rat pancreatic acinar cells may be an important signaling cascade. In this study, we show in rat dispersed pancreatic acini CCK-8 rapidly stimulates tyrosine phosphorylation of p130(Cas), reaching a maximum (6.6 +/- 1. 4)-fold increase with a half-maximal effect at 0.3 nM. Activation of protein kinase C by TPA or increases in [Ca2+]i by the calcium ionophore A23187 stimulated p130(Cas) phosphorylation. Blockade of CCK increases in [Ca2+]i or PKC activity did not alter CCK-8-stimulated p130(Cas) phosphorylation; however, simultaneous blockage of both cascades caused a 50% inhibition. Partial inactivation by C. botulinum toxin of the small GTP-binding protein Rho caused a 41 +/- 12% decrease in the CCK-stimulated p130(Cas) phosphorylation. Disruption of the actin cytoskeleton with cytochalasin D, but not the microtubule network with colchicine, completely inhibited CCK-8-stimulated p130(Cas) phosphorylation. Total p130(Cas) under basal conditions was largely localized (70 +/- 2%) in the membrane fraction, and stimulation with CCK-8 induced total p130(Cas) translocation from the cytosolic fraction. CCK stimulation also caused a (5 +/- 1)-fold increase in p130(Cas) tyrosine phosphorylated in the plasma membrane. Treatment with tyrphostin B44 inhibited CCK-8-stimulated p130(Cas) phosphorylation, but it had no effect on p130(Cas) translocation. CCK-8 caused rapid formation of a p130(Cas)-Crk complex. In conclusion, our results demonstrate CCKA receptor activation causes rapid tyrosine phosphorylation of p130(Cas) through PLC-dependent and -independent mechanisms that require the participation of the small GTP-binding protein Rho and the integrity of the actin cytoskeleton, but not the microtubule network. Moreover, CCKA receptor activation causes translocation of p130(Cas) to the membrane and an increase in membrane tyrosine-phosphorylated p130(Cas). The translocation to the membrane does not require antecedent tyrosine phosphorylation. CCKA activation promotes the rapid formation of a p130(Cas)-Crk complex. These results suggest that p130(Cas) is likely an important modulator of downstream signals activated by CCK-8, possibly involved in regulating numerous cellular effects, such as effects on cell growth or cell shape.
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PMID:CCKA receptor activation stimulates p130(Cas) tyrosine phosphorylation, translocation, and association with Crk in rat pancreatic acinar cells. 993 Oct 15


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