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)

Signalling proteins such as phospholipase C-gamma (PLC-gamma) or GTPase-activating protein (GAP) of ras contain conserved regions of approximately 100 amino acids termed src homology 2 (SH2) domains. SH2 domains were shown to be responsible for mediating association between signalling proteins and tyrosine-phosphorylated proteins, including growth factor receptors. Nck is an ubiquitously expressed protein consisting exclusively of one SH2 and three SH3 domains. Here we show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues. Similar stimulation of Nck phosphorylation was detected upon activation of rat basophilic leukemia RBL-2H3 cells by cross-linking of the high-affinity immunoglobulin E receptors (Fc epsilon RI). Ligand-activated, tyrosine-autophosphorylated platelet-derived growth factor or epidermal growth factor receptors were coimmunoprecipitated with anti-Nck antibodies, and the association with either receptor molecule was mediated by the SH2 domain of Nck. Addition of phorbol ester was also able to stimulate Nck phosphorylation on serine residues. However, growth factor-induced serine/threonine phosphorylation of Nck was not mediated by protein kinase C. Interestingly, approximately fivefold overexpression of Nck in NIH 3T3 cells resulted in formation of oncogenic foci. These results show that Nck is an oncogenic protein and a common target for the action of different surface receptors. Nck probably functions as an adaptor protein which links surface receptors with tyrosine kinase activity to downstream signalling pathways involved in the control of cell proliferation.
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PMID:The SH2 and SH3 domain-containing Nck protein is oncogenic and a common target for phosphorylation by different surface receptors. 133 47

Products of the ras gene family, termed p21ras, are GTP-binding proteins that have been implicated in signal transduction via receptors encoding tyrosine kinase domains. Recent findings have defined a superfamily of hemopoietin receptors that includes receptors for a number of interleukins and colony-stimulating factors. The intracellular portions of these receptors show only restricted homologies, have no tyrosine kinase domain, and provide no clues to the mode of signal transduction. However, in most cases the factors stimulate tyrosine phosphorylation. We demonstrate here that ligand-induced activation of the interleukin (IL)-2, IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptors resulted in activation of p21ras in various hemopoietic cell lines. The only cytokine tested that binds to a hemopoietin receptor and that did not activate p21ras was IL-4. Activation of p21ras was also observed in response to Steel factor, which stimulates the endogenous tyrosine kinase activity of the c-kit receptor, as well as with phorbol esters, which activate protein kinase C. Experiments with protein kinase inhibitors implicated tyrosine kinase activity, but not protein kinase C activity, as the upstream signal in p21ras activation via these growth factor receptors. Attempts to demonstrate tyrosine phosphorylation of the p21ras GTPase-activating protein (GAP) were negative, suggesting that phosphorylation of GAP may not be the major mechanism for regulation of p21ras activity by tyrosine kinases.
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PMID:p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein. 137 79

An RNA identified by differential cDNA cloning (HAT-2) is highly enriched in canary forebrain in areas associated with the control of complex learned behaviors and higher perceptual processes. The nucleotide sequence predicts a protein that is 96% identical to the product of the n-chimaerin gene isolated from human brain and contains two identifiable domains suggesting a novel role in signal transduction processes. One domain is similar to the sequence in protein kinase C which mediates diacylglycerol binding and regulation. The second domain is similar to a portion of BCR, a GTPase-activating protein encoded by the breakpoint cluster region gene. In male canaries examined during the song season, HAT-2 RNA shows variable expression within the song control circuit, and is notably less abundant in the three nuclei which concentrate androgens (HVC, RA and L-MAN). A fundamental function in the vertebrate forebrain and a possible role in the regulation of neural plasticity are suggested by the conserved structure and pattern of expression of this gene in the brain.
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PMID:Differential regulation in the avian song control circuit of an mRNA predicting a highly conserved protein related to protein kinase C and the bcr oncogene. 137 99

Proteins of the ras family of oncogenes have been implicated in signal transduction pathways initiated by protein kinase C (PKC) and by tyrosine kinase oncogenes and receptors, but the role that ras plays in these diverse signalling systems is poorly defined. The activity of ras proteins has been shown to be controlled in part by a cellular protein, GAP (GTPase-activating protein), that negatively regulates p21c-ras by enhancing its intrinsic GTPase activity. Thus, overexpression of GAP provides a tool for determining the step(s) in signal transduction dependent on p21c-ras activity. In this paper, we report that overexpression of GAP blocks the phorbol ester (tetradecanoyl phorbol acetate [TPA])-induced activation of p42 mitogen-activated protein kinase (p42mapk), c-fos expression, and DNA synthesis. GAP overexpression did not block responses to serum or fluoroaluminate. Moreover, not all biochemical events elicited by TPA were affected by GAP overexpression, as increased glucose uptake and phosphorylation of MARCKS, a major PKC substrate, occurred normally. Reduction of GAP expression to near normal levels restored the ability of the cells to activate p42mapk in response to TPA. These findings suggest that ras and GAP together play a key role in a PKC-dependent signal transduction pathway which leads to p42mapk activation and cell proliferation.
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PMID:Regulation of tetradecanoyl phorbol acetate-induced responses in NIH 3T3 cells by GAP, the GTPase-activating protein associated with p21c-ras. 154 25

External signals that control the activity of proteins encoded by the ras proto-oncogenes have not previously been characterized. It is now shown that stimulation of the antigen receptor of T lymphocytes causes a rapid activation of p21ras. The mechanism seems to involve a decrease in the activity of GAP, the GTPase-activating protein, on stimulation of protein kinase C. In lymphocytes, p21ras may therefore be an important mediator of the action of protein kinase C.
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PMID:Stimulation of p21ras upon T-cell activation. 220 20

Stimulation of the activity of protein kinase C by pretreatment of cells with phorbol esters was tested for its ability to inhibit signaling by four members of the insulin receptor family, including the human insulin and insulin-like growth factor-I receptors, the human insulin receptor-related receptor, and the Drosophila insulin receptor. Activation of overexpressed protein kinase C alpha resulted in a subsequent inhibition of the ligand-stimulated increase in antiphosphotyrosine-precipitable phosphatidylinositol 3-kinase mediated by the kinase domains of all four receptors. This inhibition varied from 97% for the insulin receptor-related receptor to 65% for the Drosophila insulin receptor. In addition, the activation of protein kinase C alpha inhibited the in situ ligand-stimulated increase in tyrosine phosphorylation of the GTPase-activating protein-associated p60 protein as well as Shc mediated by these receptors. The mechanism for this inhibition was further studied in the case of the insulin-like growth factor-I receptor. Although the in situ phosphorylation of insulin-receptor substrate-1 and p60 by this receptor was inhibited by prior stimulation of protein kinase C alpha, the in vitro tyrosine phosphorylation of these two substrates by this receptor was not decreased by prior stimulation of the protein kinase C alpha in the cells that served as a source of the substrates. Finally, the insulin-like growth factor-I-stimulated increase in cell proliferation was found to be inhibited by prior activation of protein kinase C alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of protein kinase C alpha inhibits signaling by members of the insulin receptor family. 754 65

A M(r) 190,000 protein (p190) functions as a GTPase-activating protein (GAP) for Rho and Rac family proteins, which are involved in regulating cytoskeletal actin and membrane ruffling. Tyrosine-phosphorylated p190 also complexes with rasGAP, a regulator of Ras activity, thus possibly linking Ras and Rho pathways. Leukemic cells induced to differentiate along myelomonocytic lineages have increased filamentous actin (as evidenced by phalloidin staining) and extended pseudopodia, and become irregularly shaped and flattened, suggesting altered Rho and Rac function. We, therefore, hypothesized that changes in p190 and its association with rasGAP are an integral part of these shape changes. During phorbol 13-myristate 25-acetate-induced monocytic differentiation of HL60 promyelocytic and RWLeu4 chronic myelogenous leukemic cells, the total amount of p190 decreases rapidly but returns to initial levels by 12 h. In RWLeu4, this was accompanied by commensurate changes in p190 tyrosine phosphorylation and association with p120 type I rasGAP. Association of p190 and type I rasGAP was demonstrated by immunoprecipitation with antibodies to either protein. An additional band at M(r) 100,000 (p100) was detected in immunoprecipitates after 12 h of phorbol 13-myristate 25-acetate treatment. Reverse transcription-PCR and immunoblot analyses suggest that p100 is type II rasGAP, an alternatively spliced product of p120 type I rasGAP. p100 was expressed only in response to direct protein kinase C activators, but all classes of differentiation agents increased tyrosine-phosphorylated p190. Rho and Rac are known to be involved in regulating actin polymerization. The results presented here show that the association of p190 with type I rasGAP parallels increases in actin polymerization and cell adhesion. This suggests a role for p190-rasGAP interactions in phorbol 13-myristate 25-acetate-induced cytoskeletal reorganization.
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PMID:Changes in tyrosine-phosphorylated p190 and its association with p120 type I and p100 type II rasGAPs during myelomonocytic differentiation of human leukemic cells. 775 72

In the present studies, insulin was found to stimulate in a rat hepatoma cell line (called FAO cells) the tyrosine phosphorylation of the 60-kilodalton p21ras GTPase-activating protein (GAP)-associated protein called p60. Surprisingly, the tyrosine phosphorylation of this protein was also almost equally stimulated by an activator of protein kinase C (PKC), the phorbol ester phorbol 12-myristate 13-acetate (PMA). The tyrosine phosphorylation of p60 induced by either agent correlated with the formation of the GAP-p60 complex in situ and an increase in the ability of p60 to directly bind to the SH2 domain of GAP in vitro. Several lines of evidence indicated that the PMA-induced tyrosine phosphorylation of p60 occurred through a different mechanism than that induced by insulin. First, the stimulation of tyrosine phosphorylation of p60 by maximal concentrations of the two agents was almost additive. Second, down-regulation of PKC or pretreatment with a specific inhibitor of PKC abolished the ability of PMA to stimulate tyrosine phosphorylation of p60 but had no effect on the insulin stimulation. And third, long-term pretreatment with insulin abolished the insulin response but did not affect the response to PMA. The PMA effect did seem to be mediated via a tyrosine kinase, since it was blocked by quercetin, an inhibitor of tyrosine kinases. These results indicate that both PMA and insulin can equally stimulate in FAO cells the tyrosine phosphorylation of p60 and its association with GAP, although these two agents seem to act via different signaling systems.
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PMID:Activation of protein kinase C stimulates the tyrosine phosphorylation and guanosine triphosphatase-activating protein association of p60 in rat hepatoma cells. 783 79

Platelet-derived growth factor (PDGF) stimulates phosphatidylcholine hydrolysis via phospholipase D (PLD) in several tissues. To determine whether PLD activation is dependent on phosphoinositide hydrolysis by phospholipase C (PLC), we measured the formation of phosphatidylbutanol (PtdBut), in TRMP cells overexpressing wild type or various mutant PDGF receptors. Both PLC and PLD were stimulated by PDGF in cells expressing wild type receptors whereas they were not in cells expressing kinase-deficient (R634) receptors. These data indicate that tyrosine phosphorylation is required for activation of both PLC and PLD. Mutation of Tyr-1021 of the PDGF receptor to Phe caused loss of PDGF stimulation of both PLC and PLD. On the other hand, a mutant PDGF receptor that was able to bind PLC gamma 1 but not other signaling proteins (including the Ras GTPase-activating protein, phosphatidylinositol 3-kinase, and a SH2-containing phosphotyrosine phosphatase (Syp)) restored the stimulatory effect of PDGF on PLC and PLD. Furthermore, receptors in which association with the GTPase-activating protein, phosphatidylinositol 3-kinase, or Syp was individually restored were unable to mediate PDGF stimulation of PLC or PLD. These data indicate that these other signal transduction proteins are not involved in the activation of PLD by PDGF. Treatment of the cells with the protein kinase C inhibitor, Ro-31-8220, and depletion of cellular protein kinase C by pretreatment with 4 beta-phorbol 12-myristate 13-acetate resulted in loss of PLD activation by PDGF indicating a PKC-dependent mechanism. In summary, these results indicate that activation of PLC gamma 1 and protein kinase C are necessary for the stimulation of PLD by PDGF and provide no evidence for alternative mechanisms.
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PMID:Activation of phospholipase C-gamma is necessary for stimulation of phospholipase D by platelet-derived growth factor. 796 10

The effect of site-specific mutations in the mouse platelet-derived growth factor (PDGF) beta-receptor on activation of the Na+/H+ exchanger was examined in normal murine mammary gland epithelial (NMuMG) and Chinese hamster ovary (CHO) cells. These cells, which do not normally express PDGF receptors, were stably transfected with PDGF beta-receptor cDNA. Intracellular pH and Ca2+ were monitored using fluorescent probes. In both NMuMG and CHO cells expressing wild-type PDGF beta-receptors, PDGF B/B activated the amiloride-sensitive Na+/H+ exchanger. In both cell types, cell alkalinization was reduced by approximately 50% with a receptor mutant Y708F,Y719F which cannot bind phosphatidylinositol (PI) 3'-kinase. An inhibitor of PI 3'-kinase, LY294002, also inhibited alkalinization by 43% in cells with wild-type, but not Y708F,Y719F receptors. PDGF-induced intracellular Ca2+ release was not affected by this mutation. Both alkalinization and Ca2+ release were reduced by nearly 100% with the mutant Y977F,Y989F, which cannot bind phospholipase C gamma (PLC gamma). Y739F, a mutant that fails to bind the GTPase-activating protein did not affect PDGF-induced alkalinization. In protein kinase C (PKC) down-regulated NMuMG cells (wild-type receptor), PDGF no longer activated the Na+/H+ exchanger. In contrast, in PKC down-regulated CHO cells (wild-type receptor), PDGF-induced alkalinization was attenuated by only 37%. This residual activity was unaffected by the Y708F,Y719F mutation, but was completely eliminated by removal of medium Ca2+. These findings indicate that phospholipase C gamma is essential for activation of Na+/H+ exchange. PI 3'-kinase participates in PKC-dependent activation of Na+/H+ exchange by PDGF. In CHO cells, there is a second, Ca(2+)-dependent mechanism for activation of the exchanger.
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PMID:Activation of Na+/H+ exchange by platelet-derived growth factor involves phosphatidylinositol 3'-kinase and phospholipase C gamma. 798 95


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