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)

An obligatory step in the activation of Signal Transducers and Activators of Transcription (STATs) by cytokines is their docking to specific receptors via phosphotyrosines. However, this model does not address whether STATs pre-associate with their corresponding receptor or exist free in the cytoplasm before receptor activation. In this report, we demonstrate that pre-association of STAT1 with the receptor is required for type I interferon (IFN) signaling. Interestingly, the interaction between the human type I IFN receptor and STAT1 is not direct but mediated by the adapter protein receptor for activated protein kinase C (RACK1). Disruption of the IFNalpha receptor-RACK1 interaction abolishes not only IFNalpha-induced tyrosine phosphorylation of STAT1 but also activation of STAT2, indicating that RACK1 plays a central role in early signaling through the Jak-STAT pathway. These findings demonstrate the involvement of RACK1 in STAT1 activation and raise the possibility that other STATs may pre-associate with cytokine receptors through similar adapter-STAT-mediated interactions.
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PMID:The WD motif-containing protein receptor for activated protein kinase C (RACK1) is required for recruitment and activation of signal transducer and activator of transcription 1 through the type I interferon receptor. 1130 23

The synaptic vesicle protein, synaptotagmin, has been hypothesized to mediate several functions in neurotransmitter release including calcium sensing, vesicle recycling, and synaptic vesicle docking. These hypotheses are based on evidence from in vitro binding assays, peptide and antibody injection experiments, and genetic knockout studies. Synaptotagmin contains two domains that are homologous to the calcium ion (Ca(2+))-binding C2 domain of protein kinase C. The two C2 domains of synaptotagmin have broadly differing ligand-binding properties. We have focused on the second C2 domain (C2B) of synaptotagmin I, in particular, on a series of conserved lysine residues on beta-strand 4 of C2B. This polylysine motif binds clathrin-adapter protein AP-2, neuronal calcium channels, and inositol high polyphosphates. It also mediates Ca(2+)-dependent oligomerization. To investigate the importance of these lysine residues in synaptic transmission, we have introduced synaptotagmin I (syt) transgenes harboring specific polylysine motif mutations into flies otherwise lacking the synaptotagmin I protein (syt(null)). Electrophysiological analyses of these mutants revealed that evoked transmitter release is decreased by approximately 36% and that spontaneous release is increased approximately twofold relative to syt(null) flies that express a wild type syt transgene. Synaptotagmin expression in both the mutant and the wild type transgenic lines was equivalent, as measured by semiquantitative Western blot analysis. Thus, the alteration in synaptic transmission was due to the mutation and not to the level of synaptotagmin expression. We conclude that synaptotagmin interactions mediated by the C2 B polylysine motif are required to attain full synaptotagmin function in vivo.
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PMID:Mutations in the second C2 domain of synaptotagmin disrupt synaptic transmission at Drosophila neuromuscular junctions. 1141 42

Grb2-associated binder-1 (Gab1) is an adapter protein related to the insulin receptor substrate family. It is a substrate for the insulin receptor as well as the epidermal growth factor (EGF) receptor and other receptor-tyrosine kinases. To investigate the role of Gab1 in signaling pathways downstream of growth factor receptors, we stimulated rat aortic vascular smooth muscle cells (VSMC) with EGF and platelet-derived growth factor (PDGF). Gab1 was tyrosine-phosphorylated by EGF and PDGF within 1 min. AG1478 (an EGF receptor kinase-specific inhibitor) failed to block PDGF-induced Gab1 tyrosine phosphorylation, suggesting that transactivated EGF receptor is not responsible for this signaling event. Because Gab1 associates with phospholipase Cgamma (PLCgamma), we studied the role of the PLCgamma pathway in Gab1 tyrosine phosphorylation. Gab1 tyrosine phosphorylation by PDGF was impaired in Chinese hamster ovary cells expressing mutant PDGFbeta receptor (Y977F/Y989F: lacking the binding site for PLCgamma). Pretreatment of VSMC with (a specific PLCgamma inhibitor) inhibited Gab1 tyrosine phosphorylation as well, indicating the importance of the PLCgamma pathway. Gab1 was tyrosine-phosphorylated by phorbol ester to the same extent as PDGF stimulation. Studies using antisense protein kinase C (PKC) oligonucleotides and specific inhibitors showed that PKCalpha and PKCepsilon are required for Gab1 tyrosine phosphorylation. Binding of Gab1 to the protein-tyrosine phosphatase SHP2 and phosphatidylinositol 3-kinase was significantly decreased by PLCgamma and/or PKC inhibition, suggesting the importance of the PLCgamma/PKC-dependent Gab1 tyrosine phosphorylation for the interaction with other signaling molecules. Because PDGF-mediated ERK activation is enhanced in Chinese hamster ovary cells that overexpress Gab1, Gab1 serves as an important link between PKC and ERK activation by PDGFbeta receptors in VSMC.
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PMID:Protein kinase C-alpha and protein kinase C-epsilon are required for Grb2-associated binder-1 tyrosine phosphorylation in response to platelet-derived growth factor. 1194 May 81

The 14-3-3 protein is a family of highly conserved acidic proteins found in a wide range of eukaryotes from yeast to mammals. 14-3-3 acts as an adapter protein and interacts with signaling molecules including protein kinase C (PKC). Although 14-3-3 zeta was originally characterized as an endogenous PKC inhibitor, it was reported to activate PKC in vitro, but the in vivo regulation of PKC by 14-3-3 is still not well understood. To examine the regulation of PKC by 14-3-3 in the cell, we have generated a sub-cell line, PC12-B3, that stably expresses FLAG epitope-tagged 14-3-3 zeta isoform in PC12 cells. Here we show that PKC-alpha and PKC-epsilon become associated with 14-3-3 zeta when the cells are neuronally differentiated by nerve growth factor. We found that the immunoprecipitate by anti-FLAG antibody contains constitutive and autonomous Ca(2+)-independent non-classical PKC activity. In contrast, the FLAG immunoprecipitate has no Ca(2+)-dependent classical PKC activity despite the fact that PKC-alpha is present in the FLAG immunoprecipitate from differentiated PC12-B3 cells. Our results show that the association with 14-3-3 zeta has distinct effects on classical PKC and non-classical PKC activity.
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PMID:Selective association of protein kinase C with 14-3-3 zeta in neuronally differentiated PC12 Cells. Stimulatory and inhibitory effect of 14-3-3 zeta in vivo. 1195 Aug 41

Regulation of mast cell degranulation is dependent on the subtle interplay of cellular signaling proteins. The Src homology 2 (SH2) domain-containing inositol-5'-phosphatase (SHIP), which acts as the gatekeeper of degranulation, binds via both its SH2 domain and its phosphorylated NPXY motifs to the adapter protein Shc via the latter's phosphorylated tyrosines and phosphotyrosine-binding domain, respectively. This theoretically leaves Shc's SH2 domain available to bind proteins, which might be part of the SHIP/Shc complex. In a search for such proteins, protein kinase C-delta (PKC-delta) was found to coprecipitate in mast cells with Shc and to interact with Shc's SH2 domain following antigen or pervanadate stimulation. Phosphorylation of PKC-delta's Y(332), most likely by Lyn, was found to be responsible for PKC-delta's binding to Shc's SH2 domain. Using PKC-delta(-/-) bone marrow-derived mast cells (BMMCs), we found that the antigen-induced tyrosine phosphorylation of Shc was similar to that in wild-type (WT) BMMCs while that of SHIP was significantly increased. Moreover, increased translocation of PKC-delta to the membrane, as well as phosphorylation at T505, was observed in SHIP(-/-) BMMCs, demonstrating that while PKC-delta regulates SHIP phosphorylation, SHIP regulates PKC-delta localization and activation. Interestingly, stimulation of PKC-delta(-/-) BMMCs with suboptimal doses of antigen yielded a more sustained calcium mobilization and a significantly higher level of degranulation than that of WT cells. Altogether, our data suggest that PKC-delta is a negative regulator of antigen-induced mast cell degranulation.
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PMID:Protein kinase C-delta is a negative regulator of antigen-induced mast cell degranulation. 1202 11

The neurotrophin nerve growth factor (NGF) supports neuronal survival by activating the transcription factor nuclear factor-kappaB (NF-kappaB). We report here, for the first time, the identification of p75-associated kinase that mediates NGF-driven NF-kappaB activation. Using co-immunoprecipitation, we demonstrate an NGF-dependent association of interleukin 1 receptor-associated kinase (IRAK) with the p75 neurotrophin receptor in PC12 cells. Our results reveal that IRAK is recruited to the p75-NGF receptor leading to formation of a complex between IRAK, atypical protein kinase C interacting protein, p62, and TRAF6. Activation of NF-kappaB occurs predominantly through the p75 receptor, and TrkA activity suppresses NF-kappaB activation and retards IkappaBbeta degradation. In addition, we observe a requirement for the kinase activity of IRAK in mediating NGF-induced NF-kappaB activation, recruitment of the adapter protein p62 to the p75 receptor, and cell survival. Moreover, p75-IRAK-mediated kappaB activation and the recruitment of IKKbeta, but not IKKalpha, to the receptor require p62. Altogether, our data provide novel information regarding the proximal components involved in p75 receptor signaling and underscore the importance of the atypical PKC interacting protein p62 in this process.
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PMID:Identification of interleukin 1 receptor-associated kinase as a conserved component in the p75-neurotrophin receptor activation of nuclear factor-kappa B. 1203 7

Hyaluronan (HA) is a large nonsulfated glycosaminoglycan and an important regulator of angiogenesis, in particular, the growth and migration of vascular endothelial cells. We have identified some of the key intermediates responsible for induction of mitogenesis and wound recovery. Treatment of bovine aortic endothelial cells with oligosaccharides of hyaluronan (o-HA) resulted in rapid tyrosine phosphorylation and plasma membrane translocation of phospholipase Cgamma1 (PLCgamma1). Cytoplasmic loading with inhibitory antibodies to PLCgamma1, Gbeta, and Galpha(i/o/t/z) inhibited activation of extracellular-regulated kinase 1/2 (ERK1/2). Treatment with the Galpha(i/o) inhibitor, pertussis toxin, reduced o-HA-induced PLCgamma1 tyrosine phosphorylation, protein kinase C (PKC) alpha and beta1/2 membrane translocation, ERK1/2 activation, mitogenesis, and wound recovery, suggesting a mechanism for o-HA-induced angiogenesis through G-proteins, PLCgamma1, and PKC. In particular, we demonstrated a possible role for PKCalpha in mitogenesis and PKCbeta1/2 in wound recovery. Using antisense oligonucleotides and the Ras farnesylation inhibitor FTI-277, we showed that o-HA-induced bovine aortic endothelial cell proliferation, wound recovery, and ERK1/2 activation were also partially dependent on Ras activation, and that o-HA-stimulated tyrosine phosphorylation of the adapter protein Shc, as well as its association with Sos1. Binding of Src to Shc was required for its activation and for Ras-dependent activation of ERK1/2, cell proliferation, and wound recovery. Neither Src nor Ras activation was inhibited by pertussis toxin, suggesting that their activation was independent of heterotrimeric G-proteins. However, the specific Src kinase inhibitor PP2 inhibited Gbeta subunit co-precipitation with PLCgamma1, suggesting a possible role for Src in activation of PLCgamma1 and interaction between two distinct o-HA-induced signaling pathways.
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PMID:Angiogenic oligosaccharides of hyaluronan induce multiple signaling pathways affecting vascular endothelial cell mitogenic and wound healing responses. 1219 65

Integrin receptor signals are costimulatory for mitogenesis with the T-cell receptor during T-cell activation. A subset of integrin receptors can link to the adapter protein Shc and provide a mitogenic stimulus. Using a combination of genetic and pharmacological approaches, we show herein that integrin signaling to Shc in T cells requires the receptor tyrosine phosphatase CD45, the Src family kinase member Lck, and protein kinase C. Our results suggest a model in which integrin-dependent serine phosphorylation of Lck is the critical step that determines the efficiency of Shc tyrosine phosphorylation in T cells. Serine phosphorylation of Lck is dependent on PKC and is also linked to CD45 dephosphorylation. Mutants of Lck that cannot be phosphorylated on the critical serine residues do not signal efficiently to Shc and have greatly reduced kinase activity. This signaling from integrins to Lck may be an important step in the costimulation with the T-cell receptor during lymphocyte activation.
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PMID:Integrin-mediated tyrosine phosphorylation of Shc in T cells is regulated by protein kinase C-dependent phosphorylations of Lck. 1258 38

Bradykinin (BK) has been implicated in the regulation of renal function. Activation of extracellular signal-regulated protein kinase (ERK1/2) has been demonstrated in several models of toxic or proliferative renal injury. We studied activation of ERK1/2 by BK in a cell model of the most distal part of the nephron, inner medullary collecting duct (mIMCD-3) cells. Exposure of mIMCD-3 cells to BK (10(-10)-10(-5) M) resulted in a concentration-dependent increase in tyrosine phosphorylation of ERK1/2, with maximal effect at 10(-8) M BK. ERK1/2 activation by BK was observed as early as 1 min, peaked at 5 min, and was sustained at least for 1 h. The effect of BK was mediated by the B(2) receptor and was pertussis toxin-independent. Inhibition of phospholipase C, protein kinase C, or phosphatidylinositol 3-kinase did not alter ERK1/2 activation by BK. BK-induced ERK1/2 activation was Ca(2+)-calmodulin-independent but was sensitive to genistein, an inhibitor of tyrosine kinase(s). AG1478, a specific inhibitor of epidermal growth factor receptor (EGFR) kinase, completely blocked the effect of BK, suggesting an essential role of EGFR in ERK1/2 activation by BK. Immunoprecipitation/Western blot studies revealed that BK stimulated tyrosine phosphorylation of EGFR, its association with an adapter molecule Grb2, and complex formation between Grb2 and the adapter protein Shc. Activation studies of monomeric G protein Ras showed that BK-induced stimulation of Ras was dependent on EGFR tyrosine kinase activity. These studies demonstrate that BK stimulates Ras-dependent activation of ERK1/2 in mIMCD-3 cells via transactivation of EGFR through a novel mechanism.
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PMID:Bradykinin B2 receptor activates extracellular signal-regulated protein kinase in mIMCD-3 cells via epidermal growth factor receptor transactivation. 1260 71

We have recently demonstrated that multiple signalling pathways are involved in thrombin-induced proliferation in rat astrocytes. Thrombin acts by protease-activated receptor-1 (PAR-1) via mitogen-activated protein kinase activity. Signalling includes both Gi/(betagamma subunits)-phosphatidylinositol 3-kinase and a Gq-phospholipase C/Ca2+/protein kinase C (PKC) pathway. In the present study, we investigated the possible protein tyrosine kinases which might be involved in thrombin signalling cascades. We found that, in astrocytes, thrombin can evoke phosphorylation of proline-rich tyrosine kinase (Pyk2) via PAR-1. This process is dependent on the increase in intracellular Ca2+ and PKC activity. Moreover, in response to thrombin stimulation Pyk2 formed a complex with Src tyrosine kinase and adapter protein growth factor receptor-bound protein 2 (Grb2), which could be coprecipitated. Furthermore, both thrombin-induced Pyk2 phosphorylation and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation can be attenuated by Src kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. From these data we conclude that PAR-1 uses Ca2+- and PKC-dependent Pyk2 to activate Src, thereby leading to ERK1/2 activation, which predominantly recruits Grb2 in rat astrocytes.
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PMID:The role of the Ca2+-sensitive tyrosine kinase Pyk2 and Src in thrombin signalling in rat astrocytes. 1261 35


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