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)

Synaptic plasticity, or long-term potentiation (LTP), of excitatory synapses in the hippocampus contributes to learning and the establishment of spatial memories. In the CA1 region, induction of LTP enhances the function of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) because of the Ca2+-calmodulin kinase II (CaMKII)-dependent phosphorylation of this subtype of glutamate receptor. Entry of Ca2+, via N-methyl-D-aspartate receptors (NMDARs), during strong synaptic stimulation provides the stimulus to trigger phosphorylation of AMPARs. However, this induction also requires activation of a protein kinase C (PKC)-dependent tyrosine kinase signal cascade and a concomitant upregulation of NMDARs. This review focuses upon NMDARs as potential targets of PKC and/or of the PKC-dependent tyrosine kinase cascade. PKC, acting via the CAKbeta/Src tyrosine kinase cascade, enhances NMDAR activation and may increase the number of receptors expressed in synapses. In contrast, direct phosphorylation of NMDARs by PKC increases the sensitivity of NMDA channel inactivation to intracellular Ca2+. In CAI neurons, PKC provides a point of convergence of control of NMDARs and synaptic plasticity for a wide variety of G-protein coupled and growth factor receptors.
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PMID:Convergence of PKC-dependent kinase signal cascades on NMDA receptors. 1155 54

Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit increased cell growth compared with normotensive Wistar-Kyoto rats (WKY). ANG II stimulates growth via G(q)-protein-coupled signaling that involves changes in cytosolic intracellular Ca(2+) concentration ([Ca(2+)](i)) and activation of protein kinase C (PKC) and mitogen-activated protein kinases. This study examines the role of the proline-rich tyrosine kinase 2 (PYK2) in hypertensive VSMC. Basal PYK2 phosphorylation in SHR VSMC was increased compared with WKY (0.44 +/- 0.02 vs. 0.20 +/- 0.02-fold). ANG II-induced activation of PYK2 in SHR VSMC was of greater magnitude (2.2 +/- 0.2-fold in SHR; 1.4 +/- 0.1-fold in WKY) and occurred more rapidly (peak activation at 2 min in SHR vs. 5 min in WKY). This effect was blocked by pretreatment with the [Ca(2+)](i) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid or the PKC inhibitor chelerythrine. Basal and ANG II-stimulated c-Fos expression was increased in SHR versus WKY VSMC. PYK2 downregulation with antisense oligonucleotides blocked ANG II-induced c-Fos expression. Increased PYK2 activation may be altered signaling cascades that regulate cell growth in hypertensive VSMC.
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PMID:Altered PYK2 phosphorylation by ANG II in hypertensive vascular smooth muscle. 1178 92

The role of G protein-coupled receptors and their ligands in intestinal epithelial cell signaling and proliferation is poorly understood. Here, we demonstrate that arginine vasopressin (AVP) induces multiple intracellular signal transduction pathways in rat intestinal epithelial IEC-18 cells via a V(1A) receptor. Addition of AVP to these cells induces a rapid and transient increase in cytosolic Ca(2+) concentration and promotes protein kinase D (PKD) activation through a protein kinase C (PKC)-dependent pathway, as revealed by in vitro kinase assays and immunoblotting with an antibody that recognizes autophosphorylated PKD at Ser(916). AVP also stimulates the tyrosine phosphorylation of the nonreceptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) and promotes Src family kinase phosphorylation at Tyr(418), indicative of Src activation. AVP induces extracellular signal-related kinase (ERK)-1 (p44(mapk)) and ERK-2 (p42(mapk)) activation, a response prevented by treatment with mitogen-activated protein kinase kinase (MEK) inhibitors (PD-98059 and U-0126), specific PKC inhibitors (GF-I and Ro-31-8220), depletion of Ca(2+) (EGTA and thapsigargin), selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (tyrphostin AG-1478, compound 56), or the selective Src family kinase inhibitor PP-2. Furthermore, AVP acts as a potent growth factor for IEC-18 cells, inducing DNA synthesis and cell proliferation through ERK-, Ca(2+)-, PKC-, EGFR tyrosine kinase-, and Src-dependent pathways.
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PMID:Vasopressin-mediated mitogenic signaling in intestinal epithelial cells. 1183 28

Stimulation of human platelets with von Willebrand factor (vWF) induces the rapid tyrosine phosphorylation of several proteins, but very little is known on the tyrosine kinases involved in this process. In the present work, we investigated and compared the activation of two related tyrosine kinases expressed in platelets: the proline-rich tyrosine kinase 2 (Pyk2) and the focal adhesion kinase (FAK). Both kinases were tyrosine phosphorylated upon vWF interaction with glycoprotein Ib-IX-V complex, but with different mechanisms. Tyrosine phosphorylation of FAK was totally dependent on thromboxane A2 production, and was inhibited by the integrin alphaIIbeta3 antagonist RGDS peptide. Moreover, chelation of intracellular calcium or inhibition of protein kinase C (PKC) totally blocked vWF-induced tyrosine phosphorylation of FAK, indicating that this event is downstream phospholipase A2 and phospholipase C activation. By contrast, tyrosine phosphorylation of Pyk2 was only partially reduced by aspirin and RGDS, and was not affected by either calcium chelation or PKC inhibition, suggesting that activation of this kinase does not require phospholipase-mediated signalling. Both FAK and Pyk2 translocated to the cytoskeleton upon vWF stimulation of human platelets by a mechanism depending on agonist-induced actin polymerisation. Prevention of cytoskeletal relocation of Pyk2 and FAK by cytochalasin D totally blocked vWF-induced tyrosine phosphorylation of both kinases. Finally, phosphorylation of Pyk2 induced by vWF, but not by thrombin, was inhibited by piceatannol, suggesting that this kinase lies downstream Syk. These results demonstrate that both Pyk2 and FAK are involved in platelet stimulation by vWF, but indicate that only Pyk2 may play a role in the early signal transduction events activated by ligand binding to glycoprotein Ib-IX-V.
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PMID:Proline-rich tyrosine kinase 2 and focal adhesion kinase are involved in different phases of platelet activation by vWF. 1191 84

The G protein-coupled receptor agonists angiotensin II (ANG II) and lysophosphatidic acid (LPA) rapidly induce tyrosine phosphorylation of the cytosolic proline-rich tyrosine kinase 2 (Pyk2) in IEC-18 intestinal epithelial cells. The combined Pyk2 tyrosine phosphorylation induced by phorbol 12,13-dibutyrate, a direct agonist of protein kinase C (PKC), and ionomycin, a Ca2+ ionophore, was equal to that induced by ANG II. Inhibition of either PKC or Ca2+ signaling attenuated the effect of ANG II and LPA, although simultaneous inhibition of both pathways failed to completely abolish Pyk2 tyrosine phosphorylation. Cytochalasin D, which disrupts stress fibers, strongly inhibited the response of Pyk2 to ANG II or LPA. The distinct Rho-associated kinase (ROK) inhibitors HA-1077 and Y-27632, as well as the Rho inhibitor Clostridium botulinum C3 exoenzyme, also significantly attenuated ANG II- and LPA-stimulated Pyk2 tyrosine phosphorylation. Simultaneous inhibition of PKC, Ca2+, and either actin assembly or ROK completely abolished the Pyk2 response. Together, these results show that ANG II and LPA rapidly induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells via separate Ca2+-, PKC-, and Rho-mediated pathways.
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PMID:ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca2+, PKC, and Rho kinase. 1199 58

The mechanism underlying the upregulation of NMDA receptor function by group I metabotropic glutamate receptors (mGluRs), including mGluR1 and 5, is not known. Here we show that in cortical neurons, brief selective activation of group I mGluRs with (S)-3,5-dihydroxy-phenylglycine (DHPG) induced a Ca(2+)-calmodulin-dependent activation of Pyk2/CAKbeta and the Src-family kinases Src and Fyn that was independent of protein kinase C (PKC). Activation of Pyk2 and Src/Fyn kinases led to increased tyrosine phosphorylation of NMDA receptor subunits 2A and B (NR2A/B) and was blocked by a selective mGluR1 antagonist, 7-(hydroxyamino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, but not an mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine. Functional linkage between mGluR1 activation and NR2A tyrosine phosphorylation through Pyk2 and Src was also demonstrated after expression of these elements in human embryonic kidney 293 cells. Supporting functional consequences, selective activation of mGluR1 by DHPG induced a potentiation of NMDA receptor-mediated currents that was blocked by inhibiting mGluR1 or Src-family kinases. Furthermore, antagonizing calmodulin or mGluR1, but not PKC, reduced the basal tyrosine phosphorylation levels of Pyk2 and Src, suggesting that mGluR1 may control the basal activity of these kinases and thus the tyrosine phosphorylation levels of NMDA receptors.
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PMID:Metabotropic glutamate receptor 1-induced upregulation of NMDA receptor current: mediation through the Pyk2/Src-family kinase pathway in cortical neurons. 1209 97

Proline-rich tyrosine kinase 2 (PYK2), structurally related to focal adhesion kinase, has been shown to play a role in signaling cascades. Endothelial cells (ECs) under hemodynamic forces increase reactive oxygen species (ROS) that modulate signaling pathways and gene expression. In the present study, we found that bovine ECs subjected to cyclic strain rapidly induced phosphorylation of PYK2 and Src kinase. This strain-induced PYK2 and Src phosphorylation was inhibited by pretreating ECs with an antioxidant N-acetylcysteine. Similarly, ECs exposed to H(2)O(2) increased both PYK2 and Src phosphorylation. An increased association of Src to PYK2 was observed in ECs after cyclic strain or H(2)O(2) exposure. ECs treated with an inhibitor to Src (PPI) greatly reduced Src and PYK2 phosphorylation, indicating that Src mediated PYK2 activation. Whereas the protein kinase C (PKC) inhibitor (calphostin C) pretreatment was shown to inhibit strain-induced NADPH oxidase activity, ECs treated with either calphostin C or the inhibitor to NADPH oxidase (DPI) reduced strain-induced ROS levels and then greatly inhibited the Src and PYK2 activation. In contrast to the activation of PYK2 and Src with calcium ionophore (ionomycin), ECs treated with a Ca(2+) chelator inhibited both phosphorylation, indicating that PYK2 and Src activation requires Ca(2+). ECs transfected with antisense to PKCalpha, but not antisense to PKCepsilon(,) reduced cyclic strain-induced PYK2 activation. These data suggest that cyclic strain-induced PYK2 activity is mediated via Ca(2+)-dependent PKCalpha that increases NADPH oxidase activity to produce ROS crucial for Src and PYK2 activation. ECs under cyclic strain thus activate redox-sensitive PYK2 via Src and PKC, and this PYK2 activation may play a key role in the signaling responses in ECs under hemodynamic influence.
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PMID:Cyclic strain activates redox-sensitive proline-rich tyrosine kinase 2 (PYK2) in endothelial cells. 1236 97

Fibronectin fragments (FN-f), including the 110-kDa fragment that binds the alpha5beta1 integrin, stimulate collagenase-3 (MMP-13) production and cartilage destruction. In the present study, treatment of chondrocytes with the 110-kDa FN-f or an activating antibody to the alpha5beta1 integrin was found to increase tyrosine autophosphorylation (Tyr-402) of the proline-rich tyrosine kinase-2 (PYK2) without significant change in autophosphorylation (Tyr-397) of focal adhesion kinase (FAK). The tyrosine kinase inhibitor tyrphostin A9, shown previously to block a PYK2-dependent pathway, blocked the FN-f-stimulated increase in MMP-13, whereas tyrphostin A25 did not. FN-f-stimulated PYK2 phosphorylation and MMP-13 production was also blocked by reducing intracellular calcium levels. Adenovirally mediated overexpression of wild type but not mutant PYK2 resulted in increased MMP-13 production. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate stimulated PYK2 phosphorylation and MMP-13 production. MMP-13 expression stimulated by either phorbol 12-myristate 13-acetate or FN-f was blocked by PKC inhibitors including the PKCdelta inhibitor rottlerin. Furthermore, PKCdelta translocation from cytosol to membrane was noted within 5 min of stimulation with FN-f. Immortalized human chondrocytes, transiently transfected with MMP-13 promoter-luciferase reporter constructs, showed increased promoter activity after FN-f treatment that was inhibited by co-transfection with either of two dominant negative mutants of PYK2 (Y402F and K457A). No inhibition was seen after cotransfection with wild type PYK2, a dominant negative of FAK (FRNK) or empty vector plasmid. FN-f-stimulated MMP-13 promoter activity was also inhibited by chemical inhibitors of ERK, JNK, and p38 mitogen-activated protein (MAP) kinases or by co-transfection of dominant negative MAP kinase mutant constructs. These studies have identified a novel pathway for the MAP kinase regulation of MMP-13 production which involves FN-f stimulation of the alpha5beta1 integrin and activation of the nonreceptor tyrosine kinase PYK2 by PKC, most likely PKCdelta
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PMID:Fibronectin fragment activation of proline-rich tyrosine kinase PYK2 mediates integrin signals regulating collagenase-3 expression by human chondrocytes through a protein kinase C-dependent pathway. 1273 Feb 23

Regulation of the PHAS-1-eukaryotic initiation factor-4E (eIF4E) complex is the rate-limiting step in the initiation of protein synthesis. This study characterized the upstream signaling pathways that mediate ANG II-dependent phosphorylation of PHAS-1 and eIF4E in vascular smooth muscle. ANG II-dependent PHAS-1 phosphorylation was maximal at 10 min (2.47 +/- 0.3 fold vs. control). This effect was completely blocked by the specific inhibitors of phosphatidylinositol 3-kinase (PI3-kinase, LY-294002), mammalian target of rapamycin, and extracellular signal-regulated kinase 1/2 (ERK1/2, U-0126) or by a recombinant adenovirus encoding dominant-negative Akt. PHAS-1 phosphorylation was followed by dissociation of eIF4E. Increased ANG II-induced eIF4E phosphorylation was observed at 45 min (2.63 +/- 0.5 fold vs. control), was maximal at 90 min (3.38 +/- 0.3 fold vs. control), and was sustained at 2 h. This effect was blocked by inhibitors of the ERK1/2 and p38 mitogen-activated protein (MAP) kinase pathways, but not by PI3-kinase inhibition, and was dependent on PKC, intracellular Ca2+, and tyrosine kinases. Downregulation of proline-rich tyrosine kinase 2 (PYK2) by antisense oligonucleotides led to a near-complete inhibition of PHAS-1 and eIF4E phosphorylation in response to ANG II. Therefore, PYK2 represents a proximal signaling intermediate that regulates ANG II-induced vascular smooth muscle cell protein synthesis via regulation of the PHAS-1-eIF4E complex.
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PMID:A role for PYK2 in ANG II-dependent regulation of the PHAS-1-eIF4E complex by multiple signaling cascades in vascular smooth muscle. 1289 Jun 45

Proline-rich tyrosine kinase 2 (PYK2) is a nonreceptor protein tyrosine kinase that links G-protein-coupled receptors to activation of MAPK cascades and cellular growth. In smooth muscle and other cell types, PYK2 activation is dependent on either Ca(2+) or protein kinase C (PKC), and we have previously shown that endothelin-1 (ET) activates PYK2 in adult and neonatal rat ventricular myocytes (NRVM). However, ET both alters intracellular Ca(2+) ([Ca(2+)](i)), and activates the novel, Ca(2+)-independent PKCs. Therefore, immunoprecipitation and western blotting experiments were used to examine the PKC and Ca(2+) dependence of PYK2 activation in NRVM. PYK2 was activated by ET (100 nM; 2-30 min) and phenylephrine (50 microM; 2-30 min), which are both hypertrophic agonists that activate Gq-coupled receptors. Moreover, adenoviral (Adv)-mediated overexpression of constitutively active (ca) Galphaq increased PYK2-Y(402) phosphorylation as early as 8 h post-infection, as compared to NRVM infected with a control Adv encoding beta-galactosidase. caGalphaq overexpression also induced PKC epsilon and PKCdelta (but not PKCalpha) translocation, followed by downregulation of both novel PKC isoenzymes. Phorbol myristate acetate (PMA; 200 nM), a direct activator of Ca(2+)-dependent and Ca(2+)-independent PKCs, activated PYK2 within 10 min, and PYK2 phosphorylation remained elevated after 30 min of stimulation. Adv-mediated overexpression of caPKC epsilon increased PYK2 phosphorylation, whereas Adv-mediated overexpression of a kinase-inactive mutant of PKC epsilon markedly inhibited ET-induced, but not basal PYK2 phosphorylation. In contrast, both basal and ET-induced PYK2 phosphorylation were blocked by treatment with the Src-family protein kinase inhibitor PP2. Although reducing [Ca(2+)](i) with either nifedipine (10 microM) or BAPTA-AM (50 microM) decreased basal PYK2 phosphorylation, it did not prevent ET-induced PYK2 activation. Furthermore, increasing [Ca(2+)](i) with ionomycin (10 microM), K(+) depolarization, or BayK8644 (1 microM) was not sufficient to further activate PYK2. These data demonstrate that ET-induced PYK2 activation is Gq, PKC epsilon, and Src dependent, describing a distinct signaling pathway leading to agonist-induced PYK2 activation in cardiomyocytes.
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PMID:Protein kinase C epsilon-dependent activation of proline-rich tyrosine kinase 2 in neonatal rat ventricular myocytes. 1296 35


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