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)

The migration of intestinal cells is important in the development and maintenance of normal epithelium, in a process that may be regulated by growth factors and cytokines. Although a number of growth factor receptors are expressed by intestinal cells, little progress has been made toward assignment of functional roles for these ligand-receptor systems. This study compares several growth factors and cytokines for their chemoattraction of the mouse small intestinal epithelial cell line. Epidermal and hepatocyte growth factors stimulated a rapid 30-fold chemotaxis of cells with delayed threefold migration toward transforming growth factor-beta1. Despite stimulating proliferation, keratinocyte, fibroblast, or insulin-like growth factors did not stimulate directed migration. Chemotaxis required tyrosine kinase and phosphatidylinositol phospholipase C activities but not protein kinase C or mitogen-activated protein kinase activity. These findings suggest that the repertoire of growth factors capable of regulating directed intestinal epithelial cell migration is limited and that a divergence exists in the signal transduction pathways for directed vs. nondirected migration.
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PMID:Epidermal and hepatocyte growth factors stimulate chemotaxis in an intestinal epithelial cell line. 1060 Jul 66

We have expressed dominant-active and dominant-negative forms of the Rho GTPases, Cdc42 and Rac, using vaccinia virus to evaluate the effects of these mutants on the signaling pathway leading to the degranulation of secretory granules in RBL-2H3 cells. Dominant-active Cdc42 and Rac enhance antigen-stimulated secretion by about twofold, whereas the dominant-negative mutants significantly inhibit secretion. Interestingly, treatment with the calcium ionophore, A23187, and the PKC activator, PMA, rescues the inhibited levels of secretion in cells expressing the dominant-negative mutants, implying that Cdc42 and Rac act upstream of the calcium influx pathway. Furthermore, cells expressing the dominant-active mutants exhibit elevated levels of antigen-stimulated IP(3) production, an amplified antigen-stimulated calcium response consisting of both calcium release from internal stores and influx from the extracellular medium, and an increase in aggregate formation of the IP(3) receptor. In contrast, cells expressing the dominant-negative mutants display the opposite phenotypes. Finally, we are able to detect an in vitro interaction between Cdc42 and PLCgamma1, the enzyme immediately upstream of IP(3) formation. Taken together, these findings implicate Cdc42 and Rac in regulating the exocytosis of secretory granules by stimulation of IP(3) formation and calcium mobilization upon antigen stimulation.
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PMID:Cdc42 and Rac stimulate exocytosis of secretory granules by activating the IP(3)/calcium pathway in RBL-2H3 mast cells. 1066 74

Tetanus toxin (TeTx) modifies Na(+)-dependent, high-affinity 5-hydroxytryptamine (5-HT, serotonin) uptake in a synaptosomal-enriched P(2) fraction from rat brain. The effect corresponds to a rapid and non-competitive uptake inhibition, and it is preceded by induction of phospholipase C (PLC) activity and translocation and down-regulation of the classical protein kinase C (PKC-alpha, -beta and -gamma) isoforms. The effects on serotonin transport and on cPKC activation were similar to the effects exhibited by phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Moreover, after treatment with TeTx, an increase in Ser- and Tyr-specific phosphorylation was found. Activation of PKC by both TeTx and TPA results in a loss of transport capacity and serotonin transporter (SERT) phosphorylation, which are abolished by coapplication of the specific PKC inhibitor bisindolylmaleimide-1. Since a specific PLCgamma1 phosphorylation prior to TeTx's inducing SERT phosphorylation was found, the studies suggest that part of the action of TeTx consists of modifying the signal cascade initiated in tyrosine kinase receptors on nerve tissue previous to its cellular internalization, resulting in transporter phosphorylation.
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PMID:Serotonin transporter phosphorylation modulated by tetanus toxin. 1111 54

PKCtheta plays an essential role in activation of mature T cells via stimulation of AP-1 and NF-kappaB, and is known to selectively translocate to the immunological synapse in antigen-stimulated T cells. Recently, we reported that a Vav/Rac pathway which depends on actin cytoskeleton reorganization mediates selective recruitment of PKCtheta to the membrane or cytoskeleton and its catalytic activation by anti-CD3/CD28 costimulation. Because this pathway acted selectively on PKCtheta, we addressed here the question of whether the translocation and activation of PKCtheta in T cells is regulated by a unique pathway distinct from the conventional mechanism for PKC activation, i.e., PLC-mediated production of DAG. Using three independent approaches, i.e., a selective PLC inhibitor, a PLCgamma1-deficient T cell line, or a dominant negative PLCgamma1 mutant, we demonstrate that CD3/CD28-induced membrane recruitment and COOH-terminal phosphorylation of PKCtheta are largely independent of PLC. In contrast, the same inhibitory strategies blocked the membrane translocation of PKCalpha. Membrane or lipid raft recruitment of PKCtheta (but not PKCalpha) was absent in T cells treated with phosphatidylinositol 3-kinase (PI3-K) inhibitors or in Vav-deficient T cells, and was enhanced by constitutively active PI3-K. 3-phosphoinositide-dependent kinase-1 (PDK1) also upregulated the membrane translocation of PKCtheta;, but did not associate with it. These results provide evidence that a nonconventional PI3-K- and Vav-dependent pathway mediates the selective membrane recruitment and, possibly, activation of PKCtheta in T cells.
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PMID:Translocation of PKC[theta] in T cells is mediated by a nonconventional, PI3-K- and Vav-dependent pathway, but does not absolutely require phospholipase C. 1195 28

The NF-kappaB activation pathway induced by T cell costimulation uses various molecules including Vav1 and protein kinase C (PKC)theta. Because Vav1 inducibly associates with further proteins including phospholipase C (PLC)gamma1 and Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76), we investigated their role for NF-kappaB activation in Jurkat leukemia T cell lines deficient for expression of these two proteins. Cells lacking SLP-76 or PLCgamma1 failed to activate NF-kappaB in response to T cell costimulation. In contrast, replenishment of SLP-76 or PLCgamma1 expression restored CD3/CD28-induced IkappaB kinase (IKK) activity as well as NF-kappaB DNA binding and transactivation. PKCtheta activated NF-kappaB in SLP-76- and PLCgamma1-deficient cells, showing that PKCtheta is acting further downstream. In contrast, Vav1-induced NF-kappaB activation was normal in SLP-76(-) cells, but absent in PLCgamma1(-) cells. CD3/CD28-stimulated recruitment of PKCtheta and IKKgamma to lipid rafts was lost in SLP-76- or PLCgamma1-negative cells, while translocation of Vav1 remained unaffected. Accordingly, recruitment of PKCtheta to the immunological synapse strictly relied on the presence of SLP-76 and PLCgamma1, but synapse translocation of Vav1 identified in this study was independent from both proteins. These results show the importance of SLP-76 and PLCgamma1 for NF-kappaB activation and raft translocation of PKCtheta and IKKgamma.
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PMID:Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa and phospholipase C gamma 1 are required for NF-kappa B activation and lipid raft recruitment of protein kinase C theta induced by T cell costimulation. 1249 21

Tamoxifen (TAM) is the endocrine therapeutic agent the most widely used in the treatment of breast cancer, and it operates primarily through the induction of apoptosis. In this study, we attempted to elucidate the non-ER mediated mechanism behind TAM treatment, involving the phospholipase C-protein kinase C (PLC-PKC) mediated phospholipase D (PLD) activation pathway, using multimodality methods. In TAM treated MCF7 cells, the PLC and PLD protein and mRNA levels increased. Phosphatidylethanol (PEt) and diacylglycerol (DAG) generation also increased, showing increased activity of PLD and PLCgamma1. Translocation of PKCalpha, from cytosol to membrane, was observed in TAM treated cells. By showing that both PKC and PLC inhibitors could reduce the effects of TAM-induced PLD activation, we confirmed the role of PKC and PLC as upstream regulators of PLD. Finally, we demonstrated that TAM treatment reduced the viability of MCF7 cells and brought about rapid cell death. From these results, we confirmed the hypothesis that TAM induces apoptosis in breast cancer cells, and that the signal transduction pathway, involving PLD, PLC, and PKC, constitutes one of the possible mechanisms underlying the non-ER mediated effects associated with TAM.
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PMID:Phospholipase C-protein kinase C mediated phospholipase D activation pathway is involved in tamoxifen induced apoptosis. 1276 85

Analysis of knockout mice and of T cells deficient for individual signaling proteins allowed the identification of novel members of the costimulation-induced NF-kappaB activation pathway while biochemical approaches started to unveil their functional mechanisms. These results show that NF-kappaB activation depends on an early wave of tyrosine phosphorylation that allows the inducible formation of multiprotein complexes containing several proteins required for NF-kappaB activation: adaptor proteins including Src homology 2 domain-containing leukocyte phosphoprotein 76 (SLP-76) and proteins with enzymatic activity, such as phospholipase C (PLC) gamma and the exchange factor Vav1. While Vav1 contributes to Rac-dependent reorganization of the actin cytoskeleton, activated PLCgamma1 generates the protein kinase C (PKC) activator diacylglycerol. In T cells, the novel PKC isoform PKCtheta is indispensable for NF-kappaB activation and its enzymatic activity depends on recruitment to the immunological synapse. Downstream from PKCtheta, the caspase recruitment domain (CARD) proteins CARD11/CARMA1 and Bcl10 relay T cell receptor-derived signals to the IkappaB kinase (IKK) complex. Many members of the NF-kappaB activation cascade, including the IKKs, are either constitutively or inducibly translocated to the lipid raft fraction, showing a highly organized spatial distribution of these NF-kappaB activating proteins.
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PMID:NF-kappaB activation pathways induced by T cell costimulation. 1465 80

Constitutive overexpression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a key oncogenic event in anaplastic large-cell lymphomas with the characteristic chromosomal aberration t(2;5)(p23;q35). Proteins that interact with ALK tyrosine kinase play important roles in mediating downstream cellular signals, and are potential targets for novel therapies. Using a functional proteomic approach, we determined the identity of proteins that interact with the ALK tyrosine kinase by co-immunoprecipitation with anti-ALK antibody, followed by electrospray ionization and tandem mass spectrometry (MS/MS). A total of 46 proteins were identified as unique to the ALK immunocomplex using monoclonal and polyclonal antibodies, while 11 proteins were identified in the NPM immunocomplex. Previously reported proteins in the ALK signal pathway were identified including PI3-K, Jak2, Jak3, Stat3, Grb2, IRS, and PLCgamma1. More importantly, many proteins previously not recognized to be associated with NPM-ALK, but with potential NPM-ALK interacting protein domains, were identified. These include adaptor molecules (SOCS, Rho-GTPase activating protein, RAB35), kinases (MEK kinase 1 and 4, PKC, MLCK, cyclin G-associated kinase, EphA1, JNK kinase, MAP kinase 1), phosphatases (meprin, PTPK, protein phosphatase 2 subunit), and heat shock proteins (Hsp60 precursor). Proteins identified by MS were confirmed by Western blotting and reciprocal immunoprecipitation. This study demonstrates the utility of antibody immunoprecipitation and subsequent peptide identification by tandem mass spectrometry for the elucidation of ALK-binding proteins, and its potential signal transduction pathways.
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PMID:Identification of NPM-ALK interacting proteins by tandem mass spectrometry. 1496 12

Nestin-expressing neural progenitor cells (NPCs) have been isolated from hippocampus of brains and propagated with epidermal growth factor and basic fibroblast growth factor (bFGF). However, the underlying signaling mechanisms regulating NPC proliferation remain elusive. Here we showed that neuregulinbeta1 (NRG), like bFGF, effectively promoted the proliferation of hippocampus-derived NPCs and maintained the progenitor states of NPCs. Activation of protein kinase C (PKC), a downstream effector of phospholipase C (PLC), with 12-O-tetradecanoylphorbol-13-acetate (TPA) mimicked the NRG-induced proliferation of NPCs. The synergic effect of TPA plus NRG on neurosphere growth further prompted us to find that NRG induced NPC propagation through PLC/PKC signaling pathway. ErbB4, an important functional receptor of NRG, had an interaction with PLCgamma1 protein. In addition, inactivation of PLC pathway led to severe proliferative suppression of NPCs. Our study suggests that activation of PLC/PKC pathway plays an essential role in the NRG-induced proliferation of hippocampus-derived NPCs.
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PMID:Neuregulin induces proliferation of neural progenitor cells via PLC/PKC pathway. 1517 49

PKCtheta plays an essential role in activation of mature T cells. Here, we report that the TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells.
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PMID:Positive feedback regulation of PLCgamma1/Ca(2+) signaling by PKCtheta in restimulated T cells via a Tec kinase-dependent pathway. 1521 48


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