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)

Activating the protein-tyrosine kinase activity of v-Fps leads to the rapid transcriptional activation of the Egr-1 gene, which encodes a mitogen-responsive transcription factor. Activation of Egr-1 by v-Fps was insensitive to protein kinase C depletion, suggesting that a protein kinase C-independent signal activated by v-Fps leads to the induction of Egr-1. Expression of v-Fps in transient expression assays induced Egr-1 promoter activation. v-HaRas and v-Raf also activated the Egr-1 promoter. To characterize HaRas and Raf-1 involvement in v-Fps-induced Egr-1 expression, we used recently characterized dominant negative mutants of HaRas and Raf-1. v-Fps-induced Egr-1 promoter activation was inhibited by the dominant negative mutants of both HaRas and Raf-1. v-HaRas-induced Egr-1 promoter activation was blocked by the negative Raf-1 mutant; however, v-Raf-1-induced Egr-1 promoter activation was unaffected by the inhibitory HaRas mutant. These data suggest that v-Fps activates a protein kinase C-independent intracellular signaling pathway that is dependent on both HaRas and Raf-1, where Raf-1 functions downstream of HaRas.
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PMID:The induction of Egr-1 expression by v-Fps is via a protein kinase C-independent intracellular signal that is sequentially dependent upon HaRas and Raf-1. 133 42

We reported previously that stimulation of RBL-2H3 cells through the high-affinity IgE receptor resulted in tyrosine phosphorylation of a 72-kDa protein (pp72) that was coupled to signal transduction. In the present study, although pp72 tyrosine phosphorylation was induced only by antigen triggering, stimulation of RBL-2H3 cells by either antigen or the calcium-ionophore A23187 led to increased tyrosine phosphorylation of a 110-kDa protein (pp110). This tyrosine phosphorylated protein was also observed when RBL-2H3 cells were transfected with the G protein-coupled m3 muscarinic receptor and then stimulated to secrete with carbachol. In contrast to tyrosine phosphorylation of pp72, antigen-induced pp110 tyrosine phosphorylation required extracellular calcium, was absent in cells depleted of protein kinase C, and was detected between 1 and 5 min after stimulation. The protein-tyrosine kinase inhibitor genistein blocked both histamine release and tyrosine phosphorylation induced by A23187. Altogether, the data suggest a role for pp110 in secretion. However, protein kinase C activation induced pp110 tyrosine phosphorylation but not histamine release demonstrating that pp110 tyrosine phosphorylation alone is not sufficient for degranulation. We conclude that tyrosine phosphorylation of pp72 is associated with the early steps of IgE receptor-generated signaling, whereas pp110 tyrosine phosphorylation occurs secondary to calcium influx and protein kinase C activation.
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PMID:High-affinity IgE receptor-mediated stimulation of rat basophilic leukemia (RBL-2H3) cells induces early and late protein-tyrosine phosphorylations. 137 33

A fungal metabolite, radicicol, with a macrocyclic ring induced the reversal of transformed phenotypes of v-src-transformed fibroblasts (Rous sarcoma virus-transformed 3Y1 rat fibroblast) at a quite low concentration of 0.1 microgram/ml. Actin stress fibers reappeared in the transformed cells after treatment with radicicol. Radicicol reduced the intracellular level of autophosphorylation of p60v-src as well as the level of other tyrosine-phosphorylated proteins in a dose-dependent manner. In vitro kinase assay revealed that radicicol effectively inhibited not only autophosphorylation but also transphosphorylation activities of purified p60v-src with a concentration producing 50% inhibition of 0.1 microgram/ml. However, radicicol showed no inhibitory effect on protein kinase C or protein kinase A. These results suggest that radicicol is a novel and specific protein-tyrosine kinase inhibitor and that the decreased level of tyrosine kinase activity of p60v-src causes reversion of transformed phenotypes of Rous sarcoma virus-transformed 3Y1 rat fibroblast. Furthermore, differentiation of Friend leukemia cells, which is one of the known characteristic phenomena associated with the inhibition of tyrosine kinase, was also induced in the concentration range of 0.05-0.5 microgram/ml, suggesting that the agent is useful for the analysis of differentiation as well as the kinase-mediated signal transduction.
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PMID:Potent and specific inhibition of p60v-src protein kinase both in vivo and in vitro by radicicol. 145 81

CD4 is a cell surface glycoprotein expressed by a subset of T lymphocytes and functions to enhance T-cell activation. CD4 is noncovalently associated via the cytoplasmic domain with the protein-tyrosine kinase p56lck, a member of the src protein-tyrosine kinase family. Upon activation of protein kinase C by phorbol ester, CD4 is phosphorylated on cytoplasmic serine residues and internalized from the cell surface, and disruption of the CD4-p56lck complex occurs. The exact relationship between these events is likely to be functionally significant, as cytoplasmic-domain serine phosphorylation and internalization have been shown to regulate the function of receptors that possess intrinsic protein-tyrosine kinase activity. Here we demonstrate that p56lck slows the rate of phorbol 12-myristate 13-acetate-induced internalization of CD4 in a manner that depends on a physical association between p56lck and CD4. This decreased rate is due at least in part to a requirement for disruption of the CD4-p56lck complex prior to internalization of CD4. Furthermore, disruption of the CD4-p56lck complex appears to depend on the integrity of the cytoplasmic-domain serine at position 408, probably due to a requirement for phosphorylation.
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PMID:Disruption of the CD4-p56lck complex is required for rapid internalization of CD4. 150 68

Addition of ionophore A23187 to washed human platelets caused a time- and dose-dependent increase in the phosphotyrosyl content of 135, 124 and 76 kDa proteins. Platelets loaded with intracellular Ca2+ chelator 5,5'-demethyl-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid before addition of A23187 exhibited no protein-tyrosine phosphorylation. Replenishment of such platelets with extracellular CaCl2 restored A23187-induced protein-tyrosine phosphorylation. Upon stimulation with A23187, both aspirin and ADP scavengers-treated platelets exhibited protein-tyrosine phosphorylation without phosphoinositide hydrolysis or protein kinase C activation. Its protein-tyrosine phosphorylation was not inhibited by ML-9, a selective inhibitor of myosin light chain kinase. Genistein, a selective inhibitor of protein-tyrosine kinase, inhibited A23187-induced platelet aggregation but not secretion. These data show (a) that A23187 stimulates protein-tyrosine phosphorylation by elevation of intracellular Ca2+, (b) that A23187-induced protein-tyrosine phosphorylation is independent of formation of endoperoxides/thromboxane A2, released ADP, phosphoinositide hydrolysis, protein kinase C activation, fibrinogen binding and myosin light chain kinase, and (c) that A23187-induced protein-tyrosine phosphorylation may be involved in platelet aggregation but not in secretion. Furthermore, a synergistic effect of A23187 and protein kinase C activators in stimulating protein-tyrosine phosphorylation is suggested.
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PMID:[Protein-tyrosine phosphorylation of human platelets and its function]. 161 80

The protein predicted by the sequence of the human pim-1 proto-oncogene shares extensive homology with known serine/threonine protein kinases, and yet the human Pim-1 enzyme has previously been reported to exhibit protein tyrosine kinase activity both in vitro and in vivo. Recently a new class of protein kinases has been identified which exhibits both protein-serine/threonine and protein-tyrosine kinase activities. We therefore investigated the possibility that the human Pim-1 kinase likewise possesses such bifunctional enzymatic phosphorylating activities. A full-length human pim-1 cDNA was subcloned into the bacterial vector pGEX-2T and the Pim-1 protein expressed as a fusion product with bacterial glutathione S-transferase (GST). The hybrid GST-Pim-1 fusion protein was affinity purified on a glutathione-Sepharose column prior to treatment with thrombin for cleavage of the Pim-1 protein from the transferase. Pim-1 was purified and the identity of recombinant protein confirmed by amino-terminal sequence analysis. Pim-1 was tested for kinase activity with a variety of proteins and peptides known to be substrates for either mammalian protein-serine/threonine or protein-tyrosine kinases and was found to phosphorylate serine/threonine residues exclusively in vitro. Both the Pim-1-GST fusion protein and the isolated Pim-1 protein exhibited only serine/threonine phosphorylating activity under all in vitro conditions tested. Pim-1 phosphorylated purified mammalian histone H1 with a Km of approximately 51 microM. Additionally, Pim-1 exhibited low levels of serine/threonine autophosphorylating activity. These observations place the human Pim-1 in a small select group of cytoplasmic transforming oncogenic kinases, including the protein kinase C, the Raf/Mil, and the Mos subfamilies, exhibiting serine/threonine phosphorylating activity.
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PMID:Recombinant human pim-1 protein exhibits serine/threonine kinase activity. 171 13

The protein-tyrosine kinase (PTK) v-Fps induces protein kinase C (PKC)-dependent expression of the transformation-related 9E3 gene in chicken embryo fibroblasts (Spangler, R., Joseph, C., Qureshi, S.A., Berg, K., and Foster, D.A. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 7017-7021). We present evidence here that a GTP-binding protein (G-protein) is a component of this PKC-dependent signaling pathway. 1) A GTP analogue that stimulates G-protein-mediated signals induced 9E3 gene expression. 2) A GDP analogue that inhibits signaling through G-proteins inhibited expression of 9E3 and phosphorylation of a 67-kDa PKC substrate induced by v-Fps. The GDP analogue had no effect on phosphorylation of the PKC substrate or the expression of 9E3 induced by direct activation of PKC with phorbol ester. 3) Increased v-Fps PTK activity led to increased GTP binding to a 50-kDa protein. The molecular weight of this GTP-binding protein is consistent with the molecular weight of alpha-subunits of G-proteins of the heterotrimeric class. The data suggest that a G-protein functions upstream from PKC in a signaling pathway that connects v-Fps PTK activity to increased 9E3 gene expression.
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PMID:Evidence that a G-protein transduces signals initiated by the protein-tyrosine kinase v-Fps. 171 94

Epidermal mucous metaplasia of cultured 13-day-old chick embryonic tarsometatarsal skin can be induced by culture in medium containing retinol (20 microM) for only 8-24 h and then in a chemically defined medium without vitamins or serum for 6 days. In the induction of mucous metaplasia, retinol primarily affects the dermal cells and a signal(s) induced in the dermis by excess retinol alters epidermal differentiation toward secretory epithelium. In this work we found that Bt2cAMP (2 mM) stimulated mucous metaplasia severalfold when added to retinol-pretreated skin but inhibited epidermal mucous metaplasia when added together with retinol. Forskolin (100 microM), an activator of adenylate cyclase, also stimulated mucous metaplasia when added to retinol-pretreated skin. On the other hand, transduction in the epidermal cells of a signal(s) induced in dermal cells by excess retinol was inhibited by herbimycin A (500 ng/ml), an inhibitor of protein-tyrosine kinases, and TPA (0.1 microM), an activator of protein kinase C. Hence these findings indicated that cAMP stimulated signal-induced mucous metaplasia, and that transduction of the signal(s) in the epidermal cells required protein-tyrosine kinase and was inhibited by protein kinase C.
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PMID:Stimulation by Bt2cAMP of epidermal mucous metaplasia in retinol-pretreated chick embryonic cultured skin, and its inhibition by herbimycin A, an inhibitor for protein-tyrosine kinase. 184 33

We previously reported a molecular cloning of porcine gene syk encoding a non-receptor type 72-kDa protein-tyrosine kinase and a generation of anti-CPTK40 antibodies which could immunoprecipitate the activity of p72syk (Taniguchi et al. (1991) J. Biol. Chem. 266, 15790-15796). In this study, we have demonstrated that wheat germ agglutinin caused an increase in the autophosphorylation activity of p72syk which preceded an increase of protein-tyrosine phosphorylation observed at the same time in porcine splenocyte. The increase of p72syk activity was dose dependent and was inhibited by the coexistence of N-acetyl-D-glucosamine. Upon stimulation by the combination of 4 beta-phorbol 12-myristate 13-acetate and ionophore A23187, we could not detect the increase of activity of p72syk suggesting that the activation of p72syk was independent of protein kinase C and calcium ions.
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PMID:The lectin wheat germ agglutinin stimulates a protein-tyrosine kinase activity of p72syk in porcine splenocytes. 195 83

Ligand binding to the T-cell antigen receptor results in phosphatidylinositol hydrolysis and the resultant activation of protein kinase C, as well as the activation of a receptor-coupled protein-tyrosine kinase. As a model for tyrosine kinase activation in T cells, we used retroviral gene transfer to express the v-src oncogene in an antigen-specific murine T-cell hybridoma. Clones that expressed v-src mRNA demonstrated constitutive tyrosine phosphorylation of several cellular substrates, including the zeta chain of the T-cell receptor, and constitutive interleukin 2 production. Thus, expression of a constitutively active protein-tyrosine kinase such as pp60v-src appears to be sufficient to induce the expression of at least one gene critical to the process of T-cell activation.
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PMID:Expression of v-src in a murine T-cell hybridoma results in constitutive T-cell receptor phosphorylation and interleukin 2 production. 200 Mar 81


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