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)

In the rat medullary thick ascending limb (MTAL), hyperosmolality inhibits transepithelial HCO3- absorption (JHCO3-) by inhibiting apical membrane Na+/H+ exchange. To examine signaling mechanisms involved in this regulatory response, MTALs were isolated and perfused in vitro with 25 mM HCO3- solutions (290 mosmol/kg H2O). Osmolality was increased in lumen and bath solutions by addition of 300 mM mannitol or 75 mM NaCl. Addition of mannitol reduced JHCO3- by 60% and addition of NaCl reduced JHCO3- by 50%. With the protein tyrosine kinase (PTK) inhibitor genistein (7 microM) or herbimycin A (1 microM) in the bath, addition of mannitol reduced JHCO3- only by 11% and addition of NaCl reduced JHCO3- only by 15%. Staurosporine (10(-7) M) or forskolin (10(-6) M) in the bath had no effect on inhibition of JHCO3- by hypertonic NaCl. Genistein had no effect on inhibition of JHCO3- by vasopressin (a cyclic AMP-dependent process) or stimulation of JHCO3- by prostaglandin E2 (a protein kinase C-dependent process). Under isosmotic conditions, addition of genistein or herbimycin A to the bath increased JHCO3- by 30% through stimulation of apical membrane Na+/H+ exchange. Addition of the tyrosine phosphatase inhibitor molybdate (50 microM) to the bath reproduced the inhibition of JHCO3- observed with hyperosmolality. These data indicate that 1) the effect of hyperosmolality to inhibit MTAL HCO3- absorption through inhibition of apical membrane Na+/H+ exchange is mediated via a PTK-dependent pathway that functions independent of regulation by cyclic AMP and protein kinase C, and 2) a constitutive PTK activity inhibits apical membrane Na+/H+ exchange and HCO3- absorption under isosmotic conditions. Our results suggest that tyrosine phosphorylation is a critical step in inhibition of the apical Na+/H+ exchanger isoform NHE-3 by hyperosmolality.
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PMID:Hyperosmolality inhibits bicarbonate absorption in rat medullary thick ascending limb via a protein-tyrosine kinase-dependent pathway. 773 Mar 71

It has recently been shown that the activation of protein kinase C (PKC) induces protein tyrosine phosphorylation in osteoblast-like MC3T3-E1 cells. We previously reported that the activation of PKC stimulates phosphatidylcholine-hydrolyzing phospholipase D in these cells. In this study, we examined whether protein tyrosine kinase is involved in the PKC-induced activation of phospholipase D in MC3T3-E1 cells. Genistein, an inhibitor of protein tyrosine kinases, which by itself had little effect on choline formation, significantly suppressed the formation of choline induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of PKC, in a dose-dependent manner. Tyrphostin, an inhibitor of protein tyrosine kinases chemically distinct from genistein, also dose-dependently suppressed the TPA-induced formation of choline. Sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, significantly enhanced the TPA-induced formation of choline in a dose-dependent manner. These results strongly suggest that protein tyrosine kinase regulates phospholipase D activity at a point downstream from PKC in osteoblast-like cells.
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PMID:Tyrosine kinase regulates phospholipase D activation at a point downstream from protein kinase C in osteoblast-like cells. 775 61

The histological features of rheumatoid arthritis (RA) consist of overgrowth of synovial cells. Several growth factors that cause synovial hyperplasia have been identified in RA synovium. The basic-fibroblast growth factor (b-FGF), representing one of these growth factors, may play an important role in the pathogenesis of RA. We examined the b-FGF-mediated intracellular signal pathway involved in synovial cell growth. b-FGF-induced synovial cell growth was inhibited by protein tyrosine kinase (PTK) inhibitors, herbimycin A and genistein, but not by H7 that inhibits protein kinase C (PKC). Stimulation of synovial cells with b-FGF resulted in tyrosine phosphorylation of cellular proteins and MAP kinase activation. Our results also demonstrated that b-FGF-mediated activation of MAP kinase was inhibited by herbimycin A indicating that protein tyrosine kinase may be involved in the activation of MAP kinase in human synovial cells. However, inhibition of b-FGF-mediated MAP kinase activation by PKC downregulation did not occur.
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PMID:The role of protein kinase in human synovial fibroblast growth. 776 35

The naphthodianthrone hypericin causes a photosensitized inhibition of protein kinases involved in growth factor signalling pathways. Nanomolar concentrations of hypericin inhibit the protein tyrosine kinase activities (PTK) of the epidermal growth factor receptor and the insulin receptor, while being ineffective towards the cytosolic protein tyrosine kinases Lyn, Fgr, TPK-IIB and CSK. Photosensitized inhibition by hypericin is not restricted to receptor-PTKs since the Ser/Thr protein kinases (protein kinase CK-2, protein kinase C and mitogen-activated kinase) are also extremely sensitive to inhibition (IC50 value for protein kinase CK-2 = 6 nM). A comparison of the hypericin-mediated inhibition of the epidermal growth factor-receptor PTK and protein kinase CK-2 revealed that the inhibition is irreversible, strictly dependent upon irradiation of the enzyme-inhibitor complex with fluorescent light and likely mediated by the formation of radical intermediates (type I mechanism). Although the exact molecular basis for the selectivity of enzyme inhibition by hypericin remains unknown, our results suggest that distantly related protein kinases could still share common reactive domains for the interaction with hypericin.
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PMID:Photosensitized inhibition of growth factor-regulated protein kinases by hypericin. 778 2

The inhibition of phosphatidylinositol-3-kinase (PtdIns-3-kinase), protein kinase C and c-Src protein tyrosine kinase by a series of halogenated naphthoquinones and quinoline quinones related to the plant-derived naphthoquinones juglone and methyljuglone, which inhibit protein kinase C, has been investigated. Some of the compounds inhibited PtdIns-3-kinase at micromolar concentrations and below. PtdIns-3-kinase inhibition was time dependent and could be prevented by endogenous thiol. The compounds were only weak inhibitors of PtdIns-4-kinase. Some of the compounds inhibited protein kinase C, but c-Src protein tyrosine kinase was only weakly inhibited. In intact cells, PtdIns-3-kinase was only partly inhibited by concentrations of the halogenated quinones that inhibited cell growth. Some halogenated quinones showed in vivo antitumor activity without accompanying toxicity, while methyljuglone was without in vivo antitumor activity. Halogenated quinones may have multiple biochemical effects in the cell that could contribute to their cytotoxic and antitumor effects. Inhibition of PtdIns-3-kinase by the halogenated quinones may provide a lead for the development of more potent and specific inhibitors.
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PMID:Novel quinone antiproliferative inhibitors of phosphatidylinositol-3-kinase. 778 99

The low-affinity type-IIb IgG Fc-binding receptors (Fc gamma RIIb) are expressed on B cells. When cross-linked with mIgM Fc gamma RIIb are known to down-regulate B-cell activation by interrupting signal transduction upstream from G-protein-activated events. We have studied Fc gamma RII isoforms expressed on resting and activated B cells and the interaction of Fc gamma RIIb1 with molecules transducing the antigen receptor-mediated signals. Expression of Fc gamma RII isoforms was studied by reverse transcription and polymerase chain reaction. Resting B cells express both Fc gamma RIIb2 and Fc gamma RIIb1 isoforms. Activation with anti-IgM or IL-4 induces the splicing of Fc gamma RIIb1 mRNA, while the alternative splicing of Fc gamma RIIb2 mRNA is down-regulated, resulting in the surface expression of Fc gamma RIIb1. Functional differences were found between the two isoforms in inhibiting B-cell activation, suggesting that Fc gamma RIIb2 might influence the threshold of signals necessary for activation of resting B cells, while Fc gamma RIIb1 may regulate in later phases of antibody response. To explore the mechanism by which Fc gamma RII may uncouple antigen receptor-mediated signal transduction, we have investigated the association of signaling molecules with Fc gamma RII. Beside the protein tyrosine kinase (PTK) fyn, protein kinase C (PKC) was found to be co-isolated with Fc gamma RIIb1, suggesting a tight connection between these kinases and Fc gamma RII. We suggest that PKC might be responsible for the activation-induced phosphorylation of Fc gamma RII on serine residues.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of signaling molecules with human Fc gamma RIIb1 and the role of various Fc gamma RIIb isoforms in B-cell regulation. 779 41

The protein kinase inhibitor K-252a has been shown to promote cholinergic activity in cultures of rat spinal cord and neuronal survival in chick dorsal root ganglion cultures. To determine the mechanism by which K-252a acts as a neurotrophic factor, we examined the effects of this molecule on a human neuroblastoma cell line, SH-SY5Y. K-252a induced neurite outgrowth in a dose-dependent manner. Coincident with neurite outgrowth was the early tyrosine phosphorylation of 125- and 140-kDa proteins. The phosphorylation events were independent of protein kinase C inhibition because down-regulation of protein kinase C by long-term treatment with phorbol ester did not prevent K252a-induced tyrosine phosphorylation. Similarly, the protein kinase C inhibitors H7, GF-109203X, and calphostin C did not induce the phosphorylation. We have identified one of the phosphosubstrates as the pp125 focal adhesion protein tyrosine kinase (Fak). Induction of phosphorylation coincided with increased Fak activity and appeared to be independent of ligand/integrin interaction. The induction of Fak phosphorylation by K-252a was also observed in LA-N-5 cells and primary cultures of rat embryonic striatal cells but not in PC12 cells. The protein kinase C-independent induction of tyrosine phosphorylation and the identification of Fak as a substrate of K-252a-induced tyrosine kinase activity suggest that this compound mediates neurotrophic effects through a novel signaling pathway.
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PMID:K-252a induces tyrosine phosphorylation of the focal adhesion kinase and neurite outgrowth in human neuroblastoma SH-SY5Y cells. 783 46

Astrocytes are induced by interferon-gamma (IFN-gamma) to express class II major histocompatibility complex (MHC) antigens. Our previous studies demonstrated that IFN-gamma-initiated signaling events important for class II expression include activation of protein kinase C (PKC) and the Na+/H+ antiporter. We have extended these studies and found that protein tyrosine kinase (PTK) activity is also required for class II expression. Treatment of astrocytes with inhibitors specific for PKC and PTK blocked INF-gamma-induced class II gene transcription, mRNA expression, and protein expression. Immunoblotting and immunoprecipitation experiments demonstrated that IFN-gamma induced tyrosine phosphorylation of the p91 component of ISGF3, which is blocked by preincubation of cells with PTK inhibitors. Treatment of astrocytes with IFN-gamma and either PKC and PTK inhibitors changed the mobility and intensity of a nuclear factor, IFN-gamma-enhanced factor X, which binds to the X box of the class II MHC promoter. Taken together, these data provide evidence that activation of both PTK and PKC is required for IFN-gamma-induced expression of the class II gene.
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PMID:Role of protein kinase C and tyrosine kinase activity in IFN-gamma-induced expression of the class II MHC gene. 784 Jan 40

Human mesangial cells produce the monocyte-specific chemotactic factor monocyte chemoattractant protein-1 (MCP-1) in response to a variety of stimuli, including the pro-inflammatory cytokine interleukin-1 beta (IL-1). The intracellular signals responsible for mediating the effects of IL-1 on MCP-1 expression in human mesangial cells have not been defined. Evidence from other types of cells suggests that protein kinases are involved in MCP-1 gene regulation. We investigated the role of protein kinase pathways in mediating IL-1-induced MCP-1 expression. Activation of protein kinase C (PKC) by phorbol esters or diacyglycerol up-regulated mesangial MCP-1 message and bioactivity in a fashion similar to IL-1. However, while inhibition of PKC activity completely blocked phorbol-induced MCP-1 up-regulation, induction by IL-1 was not prevented. Inhibitors of cyclic AMP (cAMP)-dependent protein kinase (PKA) also failed to block IL-1-induced MCP-1 expression. Furthermore, increasing intracellular cAMP and activating PKA attenuated basal MCP-1 mRNA levels by 82% and blocked IL-1 induced MCP-1 expression by 88%. Finally, the role of protein tyrosine kinases was studied. The structurally distinct protein tyrosine kinase (PTK) inhibitors genistein, herbimycin A, and tyrphostin each caused a dose-dependent inhibition of the effects of IL-1 on mesangial MCP-1 activity. IL-1 treatment of mesangial cells resulted in the up-regulation of three tyrosine phosphoproteins with apparent molecular masses between 40 and 62 kD. These results suggest that the effects of IL-1 on MCP-1 expression are not mediated through PKC or cAMP-PKA, but may be transduced through PTKs.
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PMID:Role of protein kinase pathways in IL-1-induced chemoattractant expression by human mesangial cells. 786 99

Since TCR/CD3 modulation may be involved in induction of T cell tolerance to self antigens, we compared ligand-induced TCR/CD3 internalization by a CTL clone and by immature thymocytes and mature T cells from mice bearing the same TCR alpha beta as transgene. The ligand used is a monoclonal antibody (mAb) specific for the receptor expressed by the clone and transgenic mice (anti-Ti mAb). CD8+ splenocytes triggered by anti-Ti mAb internalize the ligand-TCR/CD3 complex at a low rate, through a mechanism inhibited by the protein tyrosine kinase (PTK) inhibitor genistein and by staurosporine, a potent but non selective protein kinase C (PKC) inhibitor. This pattern of inhibition was similar to that observed in the CTL clone. Anti-Ti mAb induced TCR/CD3 internalization in CD4+CD8+ thymocytes at a high rate, through a mechanism which was insensitive to either genistein or staurosporine. In the CTL clone, genistein was shown to inhibit TCR/CD3 surface redistribution preceeding internalization. To characterize the PTK possibly involved in this step, we analyzed TCR/CD3 associated kinases in mature T splenocytes and thymocytes. Kinase activities present in anti-Ti mAb immunoprecipitates phosphorylated the CD3 components gamma, delta, epsilon, and zeta in both cell types although the intensity was stronger in splenic than in thymocyte extracts, whereas the phosphorylation of 70, 14 and 12kD substrates was more pronounced in thymocytes than in splenocytes. Comparable amounts of CD3 components were coprecipitated with and phosphorylated by p56lck and p59fyn respectively, in both cell types.
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PMID:Developmental control of T-cell receptor internalization. 786 44


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