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)

FAK+, an isoform of focal adhesion kinase preferentially expressed in brain and PYK2/Cakbeta (proline-rich tyrosine kinase 2/cell adhesion kinasebeta) are two related cytoplasmic tyrosine kinases. They are candidates for coupling electrical activity and stimulation of neurotransmitter receptors to short and long-term changes in synaptic properties, cytoskeletal organization and gene expression in neurons. As the same set of stimuli appear capable of stimulating FAK and/or PYK2 in non-neuronal cells and in cell lines with neuronal characteristics, we investigated the selectivity of regulation of these two kinases in mature nervous tissue. Using rat hippocampal slices, we compared the regulation of FAK+ and PYK2 by stimuli known to be active on one or the other of these two kinases in other cell types: lysophosphatidic acid (LPA), carbachol, depolarization, and hyperosmolarity. Phosphorylation of FAK+ was markedly increased by carbachol and LPA. Carbachol effects occurred via activation of M1 muscarinic receptors and nicotinic receptors. The effects of carbachol and LPA were prevented by protein kinase C inhibitors, whereas 8-Br-cAMP attenuated the effects of carbachol but not of LPA. Tyrosine phosphorylation of PYK2 but not of FAK+ was very strongly enhanced by depolarization and hyperosmolarity. This study and our previous results show that FAK+ and PYK2 are regulated differentially in hippocampal slices: FAK+ is phosphorylated on tyrosine in response to stimulation of G protein-coupled receptors, whereas PYK2 is mainly sensitive to depolarization and hyperosmolarity. Thus, FAK+ and PYK2 may provide specific and separate links between activation of neurotransmitters receptors, depolarization and tyrosine phosphorylation in mature hippocampus.
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PMID:Differential regulation of FAK+ and PYK2/Cakbeta, two related tyrosine kinases, in rat hippocampal slices: effects of LPA, carbachol, depolarization and hyperosmolarity. 975 Nov 39

In cardiac fibroblasts, angiotensin II (Ang II) induced a rapid increase in extracellular signal regulated kinase (ERK) activity in a pertussis toxin insensitive manner. This ERK activation was abolished by the Gq-associated phospholipase C inhibitor U73122 but was insensitive to protein kinase C (PKC) inhibitors or PKC downregulation by phorbol ester. Intracellular Ca2+ chelation by BAPTA-AM or TMB-8 abolished Ang II induced ERK activation, whereas treatment with EGTA or nifedipine did not affect it. Ca2+ ionophore A23187 also induced a rapid increase in ERK activity to an extent similar to that of Ang II stimulation. Calmodulin inhibitors (W7 and calmidazolium) and tyrosine kinase inhibitors (genistein and ST638) completely blocked ERK activation by Ang II and A23187. Both Ang II and A23187 caused a rapid increase in the binding of GTP to p21(Ras), which was nearly abolished by genistein and calmidazolium. Transfection with the dominant negative mutant of Ras and the Ras inhibitor manumycin completely inhibited Ang II induced ERK activation. It was also found for the first time that cardiac fibroblasts abundantly expressed Ca2+-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK and that Ang II markedly induced its activation in a Ca2+/calmodulin-sensitive manner. Overexpression of the dominant negative mutant of Pyk2 significantly attenuated Ang II or A23187-induced ERK activities (36% and 38% inhibition compared with that in mock-transfected cells, respectively) and ERK tyrosine phosphorylation levels, as well as an increase in the binding of GTP to p21(Ras). These findings demonstrate that in cardiac fibroblasts, Ang II induced Ras/ERK activation is dominantly regulated by Gq-coupled Ca2+/calmodulin signaling and that Pyk2 plays an important role in the signal transmission for efficient activation of the Ang II induced Ras/ERK pathway.
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PMID:Role of calcium-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK in angiotensin II induced Ras/ERK signaling. 977 61

Sphingosine 1-phosphate (SphP), a metabolite of cellular sphingolipids, has been shown to induce cell proliferation by activating the mitogen-activated protein kinase (MAPK) pathway. Proline-rich tyrosine kinase 2 (Pyk2) is a novel cytosolic tyrosine kinase which mediates activation of the MAPK or c-Jun N-terminal kinase (JNK) signaling pathways in response to a variety of stimuli that elevate intracellular calcium. In this report, we show that SphP stimulates both tyrosine phosphorylation of Pyk2 and MAPK activation in a transient and dose-dependent manner in rat aortic smooth muscle cells. Further studies indicate that Pyk2 phosphorylation, but not MAPK activation, is dependent on a pertussis toxin-sensitive G-protein-coupled receptor as well as partially on actin cytoskeleton. In addition, both intracellular calcium mobilization and protein kinase C (PKC) are required for optimal Pyk2 phosphorylation while either calcium increase or PKC activation is sufficient for MAPK activation in response to SphP. Finally, we show that a tyrosine kinase(s) other than Pyk2 is necessary for MAPK activation by SphP. Together, these results suggest that SphP stimulates tyrosine phosphorylation of Pyk2 through a G-protein coupled receptor, which is dissociated from its activation of the MAPK pathway in these cells.
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PMID:Differential stimulation of proline-rich tyrosine kinase 2 and mitogen-activated protein kinase by sphingosine 1-phosphate. 982 86

PYK2/CAKbeta is a recently described cytoplasmic tyrosine kinase related to p125 focal adhesion kinase (p125(FAK)) that can be activated by a number of stimuli including growth factors, lipids, and some G protein-coupled receptors. Studies suggest PYK2/CAKbeta may be important for coupling various G protein-coupled receptors to the mitogen-activated protein kinase (MAPK) cascade. The hormone neurotransmitter cholecystokinin (CCK) is known to activate both phospholipase C-dependent cascades and MAPK signaling pathways; however, the relationship between these remain unclear. In rat pancreatic acini, CCK-8 (10 nM) rapidly stimulated tyrosine phosphorylation and activation of PYK2/CAKbeta by both activation of high affinity and low affinity CCK(A) receptor states. Blockage of CCK-stimulated increases in protein kinase C activity or CCK-stimulated increases in [Ca(2+)](i), inhibited by 40-50% PYK2/CAKbeta but not p125(FAK) tyrosine phosphorylation. Simultaneous blockage of both phospholipase C cascades inhibited PYK2/CAKbeta tyrosine phosphorylation completely and p125(FAK) tyrosine phosphorylation by 50%. CCK-8 stimulated a rapid increase in PYK2/CAKbeta kinase activity assessed by both an in vitro kinase assay and autophosphorylation. Total PYK2/CAKbeta under basal conditions was largely localized (77 +/- 7%) in the membrane fraction, whereas total p125(FAK) was largely localized (86 +/- 3%) in the cytosolic fraction. With CCK stimulation, both p125(FAK) and PYK2/CAKbeta translocated to the plasma membrane. Moreover CCK stimulation causes a rapid formation of both PYK2/CAKbeta-Grb2 and PYK2/CAKbeta-Crk complexes. These results demonstrate that PYK2/CAKbeta and p125(FAK) are regulated differently by CCK(A) receptor stimulation and that PYK2/CAKbeta is probably an important mediator of downstream signals by CCK-8, especially in its ability to activate the MAPK signaling pathway, which possibly mediates CCK growth effects in normal and neoplastic tissues.
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PMID:Cholecystokinin activates PYK2/CAKbeta by a phospholipase C-dependent mechanism and its association with the mitogen-activated protein kinase signaling pathway in pancreatic acinar cells. 1053 23

Proline-rich tyrosine kinase 2 (Pyk2) (also known as RAFTK, CAKbeta or CADTK) has been identified as a member of the focal adhesion kinase (FAK) family of protein-tyrosine kinases and it has been suggested that the mode of Pyk2 activation is distinct from that of FAK. In the present study we investigated the mode of Pyk2 activation in human platelets. When platelets were stimulated with thrombin, Pyk2, as well as FAK, was markedly tyrosine-phosphorylated, in a manner mostly dependent on alphaIIbbeta3 integrin-mediated aggregation. The residual Pyk2 tyrosine phosphorylation observed in the absence of platelet aggregation was completely abolished by pretreatment with BAPTA/AM [bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester]. The Pyk2 phosphorylation was inhibited by protein kinase C (PKC) inhibitors at concentrations that inhibited platelet aggregation. In contrast, direct activation of PKC with the active phorbol ester PMA induced the tyrosine phosphorylation of Pyk2 and FAK but only when platelets were fully aggregated with the exogenous addition of fibrinogen (the ligand for alphaIIbbeta3 integrin). Furthermore, PMA-induced Pyk2 (and FAK) tyrosine phosphorylation was also observed when platelets adhered to immobilized fibrinogen. The activation of the von Willebrand factor (vWF)--glycoprotein Ib pathway with botrocetin together with vWF failed to induce Pyk2 (and FAK) tyrosine phosphorylation. Most Pyk2 and FAK was present in the cytosol and membrane skeleton fractions in unstimulated platelets. When platelets were stimulated with thrombin, both Pyk2 and FAK were translocated to the cytoskeleton in an aggregation-dependent manner. In immunoprecipitation studies, Pyk2, as well as FAK, seemed to associate with Shc through Grb2. With the use of glutathione S-transferase fusion proteins containing Shc-SH2, Grb2-SH2, and Grb2 N-terminal and C-terminal SH3 domains, it was implied that the proline-rich region of Pyk2 (and FAK) binds to the N-terminal SH3 domain of Grb2 and that the phosphotyrosine residue of Shc binds to the SH2 domain of Grb2. Although Pyk2 and FAK have been reported to be differentially regulated in many cell types, our results suggest that, in human platelets, the mode of Pyk2 activation is mostly similar to that of FAK, in terms of alphaIIbbeta3 integrin-dependent and PKC-dependent tyrosine phosphorylation. Furthermore, Pyk2, as well as FAK, might have one or more important roles in post-aggregation tyrosine phosphorylation events, in association with the cytoskeleton and through interaction with adapter proteins including Grb2 and Shc.
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PMID:Involvement of proline-rich tyrosine kinase 2 in platelet activation: tyrosine phosphorylation mostly dependent on alphaIIbbeta3 integrin and protein kinase C, translocation to the cytoskeleton and association with Shc through Grb2. 1074 87

The stromal cell-derived factor-1 (SDF-1) is an alpha chemokine that binds to the CXCR4 receptor. Knock-out studies in mice demonstrate that this ligand-receptor pair is essential in hematopoiesis. One function of SDF-1 appears to be the regulation of migration of hematopoietic progenitor cells. We previously characterized signal transduction pathways induced by SDF-1alpha in human hematopoietic progenitors and found tyrosine phosphorylation of focal adhesion components, including the related adhesion focal tyrosine kinase (RAFTK), the adaptor molecule p130 Cas, and the cytoskeletal protein paxillin. To better understand the functional role of signaling molecules connecting the CXCR4 receptor to the process of hematopoietic migration, we studied SDF-1alpha-mediated pathways in a model hematopoietic progenitor cell line (CTS), as well as in primary human bone marrow CD34(+) cells. We observed that several other focal adhesion components, including focal adhesion kinase (FAK) and the adaptor molecules Crk and Crk-L, are phosphorylated on SDF-1alpha stimulation. Using a series of specific small molecule inhibitors, both protein kinase C (PKC) and phosphoinositide-3 kinase (PI-3K) appeared to be required for SDF-1alpha-mediated phosphorylation of focal adhesion proteins and the migration of both CTS and primary marrow CD34(+) cells, whereas the mitogen-activated protein kinases ERK-1 and -2 were not. These studies further delineate the molecular pathways mediating hematopoietic progenitor migration and response to an essential chemokine, SDF-1alpha. (Blood. 2000;95:2505-2513)
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PMID:Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C. 1075 28

Glutamate is the major excitatory neurotransmitter in the CNS. Although its role in neurons has been studied extensively, little is known about its function in astrocytes. We studied the effects of glutamate on signaling pathways in primary astrocytes. We found that the tyrosine kinase related adhesion focal tyrosine kinase (RAFTK) is tyrosine phosphorylated in response to glutamate in a time- and dose-dependent manner. This phosphorylation was pertussis toxin (PTX) sensitive and could be attenuated by the depletion of Ca2+ from intracellular stores. RAFTK tyrosine phosphorylation was mediated primarily by class I/II metabotropic glutamate receptors and depends on protein kinase C (PKC) activation. Glutamate treatment of primary astrocytes also results in a significant increase in the activity of the mitogen-activated protein kinases [extracellular signal-related kinases 1/2 (ERK1/2)]. Like RAFTK phosphorylation, ERK1/2 activation is PTX sensitive and can be attenuated by the depletion of intracellular Ca2+ and by PKC inhibition, suggesting that RAFTK might mediate the glutamate-dependent activation of ERK1/2. Furthermore, we demonstrated that glutamate stimulation of primary astrocytes leads to a significant increase in DNA synthesis. Glutamate-stimulated DNA synthesis is PTX sensitive and can be inhibited by the MAP kinase kinase inhibitor PD98059, suggesting that in primary astrocytes, glutamate might signal via RAFTK and MAP kinase to promote DNA synthesis and cell proliferation.
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PMID:Glutamate-stimulated activation of DNA synthesis via mitogen-activated protein kinase in primary astrocytes: involvement of protein kinase C and related adhesion focal tyrosine kinase. 1080 Sep 36

The NMDA subtype of the glutamate-gated channel exhibits a high permeability to Ca(2+). The influx of Ca(2+) through NMDA channels is limited by a rapid and Ca(2+)/calmodulin (CaM)-dependent inactivation that results from a competitive displacement of cytoskeleton-binding proteins from the NR1 subunit of the receptor by Ca(2+)/CaM (Zhang et al., 1998; Krupp et al., 1999). The C terminal of this subunit can be phosphorylated by protein kinase C (PKC) (Tingley et al., 1993). The present study sought to investigate whether PKC regulates Ca(2+)-dependent inactivation of the NMDA channel in hippocampal neurons. Activation of endogenous PKC by 4beta-phorbol 12-myristate 13-acetate enhanced peak (I(p)) and depressed steady-state (I(ss)) NMDA-evoked currents, resulting in a reduction in the ratio of these currents (I(ss)/I(p)). We demonstrated previously that PKC activity enhances I(P) via a sequential activation of the focal adhesion kinase cell adhesion kinase beta/proline-rich tyrosine kinase 2 (CAKbeta/Pyk2) and the nonreceptor tyrosine kinase Src (Huang et al., 1999; Lu et al., 1999). Here, we report that the PKC-induced depression of I(ss) is unrelated to the PKC/CAKbeta/Src-signaling pathway but depends on the concentration of extracellular Ca(2+). Intracellular applications of CaM reduced I(ss)/I(p) and occluded the Ca(2+)-dependent effect of phorbol esters on I(ss.) Moreover, increasing the concentration of intracellular Ca(2+) buffer or intracellular application of the inhibitory CaM-binding peptide (KY9) greatly reduced the phorbol ester-induced depression of I(ss). Taken together, these results suggest that PKC enhances Ca(2+)/CaM-dependent inactivation of the NMDA channel, most likely because of a phosphorylation-dependent regulation of interactions between receptor subunits, CaM, and other postsynaptic density proteins.
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PMID:In CA1 pyramidal neurons of the hippocampus protein kinase C regulates calcium-dependent inactivation of NMDA receptors. 1084 14

-The anti-inflammatory effects of salicylate are well known, but the intracellular mechanisms underlying those effects remain to be clarified and are not explained solely by an influence on cyclooxygenase activity. In the present study, we have used cardiac fibroblasts stimulated by either angiotensin II (Ang II) or platelet-derived growth factor (PDGF) to demonstrate an inhibitory effect of salicylate on the phosphorylation of the nonreceptor tyrosine kinases, proline-rich tyrosine kinase 2 (PYK2) and c-Src, by immunoprecipitation and immunoblotting methods. This inhibition was dose dependent, with a clear effect observed at concentrations between 5 and 20 mmol/L salicylate. Intracellular Ca(2+) chelation and protein kinase C (PKC) inhibition reduced Ang II and PDGF-induced PYK2 and c-Src phosphorylation. Salicylate significantly inhibited the phosphorylation of both of the tyrosine kinases activated by either ionophore A23187 or thapsigargin treatment, which led to an elevation of cytosolic Ca(2+). Activation of PKC by phorbol ester phosphorylated both PYK2 and Src, and this effect also was attenuated by salicylate. In contrast, salicylate had no effect on either the transactivation of the epidermal growth factor receptor by Ang II or the phosphorylation of phospholipase C-gamma by PDGF. These studies indicate a novel site of action for salicylate on PYK2 and c-Src phosphorylation and suggest that this inhibitory effect on these important signaling intermediates may be through a Ca(2+)- and PKC-dependent mechanism.
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PMID:Salicylate Inhibits Phosphorylation of the Nonreceptor Tyrosine Kinases, Proline-Rich Tyrosine Kinase 2 and c-Src. 1120 70

Hic-5 and paxillin, members of the LIM protein family, have been shown to be localized in focal adhesion and to have a role in integrin-mediated signalling. In the present study we examined the involvement of Hic-5 in human platelet activation: platelets express Hic-5 but not paxillin, whereas human umbilical-vein vascular endothelial cells and MEG-01 cells express mainly paxillin. When platelets were stimulated with thrombin, collagen or the stable thromboxane A(2) analogue U46619, Hic-5 was markedly tyrosine-phosphorylated, in a manner dependent on integrin alphaIIbbeta3-mediated aggregation. In addition, direct activation of protein kinase C with PMA resulted in tyrosine phosphorylation of Hic-5 only when platelets were fully aggregated with the exogenous addition of fibrinogen. Furthermore, PMA-induced Hic-5 tyrosine phosphorylation was also observed when platelets adhered to immobilized fibrinogen. In studies on immunoprecipitation and immunodepletion, Hic-5 seemed to associate with proline-rich tyrosine kinase 2 (Pyk2) but only marginally with focal adhesion kinase. When platelets were stimulated with thrombin, both Hic-5 and Pyk2 translocated to the cytoskeleton from the cytosol and membrane fractions in a manner dependent on alphaIIbbeta3-mediated aggregation. Finally, on stimulation with PMA, Hic-5, as well as Pyk2, translocated to the cell periphery, where a meshwork of actin filaments assembled after adhesion to immobilized fibrinogen. Our results suggest that Hic-5 might be important in platelet aggregation and adhesion, in a manner dependent on alphaIIbbeta3-mediated outside-in signalling, through association with Pyk2.
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PMID:Involvement of Hic-5 in platelet activation: integrin alphaIIbbeta3-dependent tyrosine phosphorylation and association with proline-rich tyrosine kinase 2. 1131 Nov 31


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