EC:2.7.11.13 - FACTA Search

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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunological stimulation of rat, mucosal type, mast cells (line RBL-2H3) by clustering the type I Fc(epsilon) receptor (Fc[epsilon]RI) causes a fast yet transient tyrosyl phosphorylation of several proteins. We report here the characterization of a protein-tyrosine phosphatase (PTP) involved in the very early steps coupling the Fc(epsilon)RI stimulus to the cell secretory response. We have observed earlier that a PTP activity present in one of the cells' solubilized particulate fractions is enhanced 2-3-fold upon cell stimulation by Fc(epsilon)RI clustering [Hampe, C. S. & Pecht, I. (1994) FEBS Lett. 346, 194-198]. This PTP (MpII PTP) was now isolated and purified to homogeneity and appears as a 45-kDa protein. Sequence comparison of two peptide stretches of MpII PTP with those of proteins present in the Swiss-Prot and EMBL data banks revealed no significant similarity to a known protein. Hence, we assume that the MpII PTP is a novel protein. The possible involvement of MpII PTP in the stimulus-secretion coupling cascade was investigated. Abrogation of the antigen-induced Fc(epsilon)RI clustering by an excess of monovalent hapten suppressed the Fc(epsilon)RI-mediated MpII PTP activity enhancement to the levels observed in resting cells. The activity enhancement required the presence of extracellular Ca2+ ions and was also induced by an artificial increase of the free intracellular concentration of these ions. It is apparently mediated by protein kinase C (PKC) since phorbol myristate induced an additive increase in the MpII PTP activity to that induced by antigen. Also, treatment with the PKC-specific inhibitor bisindolylmaleimide suppressed the antigen-induced MpII PTP activity enhancement. PKC involvement was further supported by the finding that the MpII PTP 45-kDa protein underwent seryl phosphorylation following antigen stimulation. This modification was found to be further enhanced by pretreatment with phorbol myristate prior to antigen stimulation.
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PMID:Purification and preliminary characterization of an Fc epsilon-receptor-activated protein-tyrosine phosphatase from mast cells. 949 73

We have studied the role of protein tyrosine phosphorylation in amylase secretion from differentiated AR4-2J cells. The secretagogue bombesin, the protein kinase C activator phorbol 12-myristate 13-acetate (PMA), and the protein-tyrosine phosphatase inhibitor pervanadate induced tyrosine phosphorylation of different proteins, including paxillin and p125(FAK), which was reduced or blocked by the tyrosine kinase inhibitors genistein and tyrphostin B56, respectively. Both PMA and pervanadate continuously increased amylase secretion with a similar time course, reaching the level of bombesin-induced amylase release after 60 min. Their effects were not additive and could be inhibited by preincubation of AR4-2J cells with genistein or tyrphostin B56, respectively. Inhibition of protein kinase C with Ro 31-8220 nearly abolished the effects of PMA, but had no effect on either pervanadate-induced protein tyrosine phosphorylation or amylase secretion. An increase in cytosolic free Ca2+ concentration by thapsigargin or A23187 caused a rapid increase in amylase release within the initial 5 min. In the presence of PMA or pervanadate, amylase secretion was further stimulated to levels comparable to those induced by bombesin after 30 min of stimulation. Inhibition of PMA-induced amylase secretion by Ro 31-8220 was less at elevated cytosolic free Ca2+ concentrations than without Ca2+. Furthermore, an increase in cytosolic free Ca2+ concentration had no effect on protein tyrosine phosphorylation in either the absence or presence of PMA or pervanadate. We therefore conclude that in the cascade of events that lead to bombesin-induced protein secretion from AR4-2J cells, protein tyrosine phosphorylation occurs downstream of protein kinase C activation. A further step in secretion that is Ca2+-dependent occurs distal to protein tyrosine phosphorylation.
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PMID:Pervanadate stimulates amylase release and protein tyrosine phosphorylation of paxillin and p125(FAK) in differentiated AR4-2J pancreatic acinar cells. 963

It has been proposed that H(2)O(2) increases tyrosine phosphorylation of cellular proteins by inhibiting protein-tyrosine phosphatase through oxidation of the cysteine residue of the enzyme essential for its catalytic activity. Tyrosine phosphorylation of the delta isoform of protein kinase C (PKC) was induced by H(2)O(2) in CHO and COS-7 cells. H(2)O(2) also induced activation of mitogen-activated protein kinase. Vanadate and molybdate, which inhibit protein-tyrosine phosphatase by binding to its active site, did not induce tyrosine phosphorylation of PKCdelta, but enhanced H(2)O(2)-induced tyrosine phosphorylation of PKCdelta in the cell. The oxoanions, however, generated the active form of mitogen-activated protein kinase. Another protein-tyrosine phosphatase inhibitor, phenylarsine oxide, which bridges the thiol residues of the enzyme, induced tyrosine phosphorylation of PKCdelta, and the reaction was enhanced by vanadate. These results suggest that inhibition of protein-tyrosine phosphatase is insufficient for induction of tyrosine phosphorylation of PKCdelta in the cells, and that presumably activation of protein-tyrosine kinase may be essential for tyrosine phosphorylation of the PKC isoform.
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PMID:H(2)O(2)-induced tyrosine phosphorylation of protein kinase cdelta by a mechanism independent of inhibition of protein-tyrosine phosphatase in CHO and COS-7 cells. 1089 55

The protein-tyrosine phosphatase CD45 is expressed on all monocytic cells, but its function in these cells is not well defined. Here we report that CD45 negatively regulates monocyte differentiation by inhibiting phorbol 12-myristate 13-acetate (PMA)-dependent activation of protein kinase C (PKC) delta. We found that antisense reduction of CD45 in U937 monocytic cells (CD45as cells) increased by 100% the ability of PMA to enlarge cell size, increase cell cytoplasmic process width and length, and induce surface expression of CD11b. In addition, reduction in CD45 expression caused the duration of peak PMA-induced MEK and extracellular signal-regulated kinase (ERK) 1/2 activity to increase from 5 min to 30 min while leading to a 4-fold increase in PMA-dependent PKCdelta activation. Importantly, PMA-dependent tyrosine phosphorylation of PKCdelta was also increased 4-fold in CD45as cells. Finally, inhibitors of MEK (PD98059) and PKCdelta (rottlerin) completely blocked PMA-induced monocytic cell differentiation. Taken together, these data indicate that CD45 inhibits PMA-dependent PKCdelta activation by impeding PMA-dependent PKCdelta tyrosine phosphorylation. Furthermore, this blunting of PKCdelta activation leads to an inhibition of PKCdelta-dependent activation of ERK1/2 and ERK1/2-dependent monocyte differentiation. These findings suggest that CD45 is a critical regulator of monocytic cell development.
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PMID:CD45 negatively regulates monocytic cell differentiation by inhibiting phorbol 12-myristate 13-acetate-dependent activation and tyrosine phosphorylation of protein kinase Cdelta. 1112 68

Midkine, a heparin-binding growth factor, plays a critical role in cell migration causing suppression of neointima formation in midkine-deficient mice. Here we have determined the molecules essential for midkine-induced migration. Midkine induced haptotaxis of osteoblast-like cells, which was abrogated by the soluble form of midkine or pleiotrophin, a midkine-homologous protein. Chondroitin sulfate B, E, chondroitinase ABC, B, and orthovanadate, an inhibitor of protein-tyrosine phosphatase, suppressed the migration. Supporting these data, the cells examined expressed PTPzeta, a receptor-type protein-tyrosine phosphatase that exhibits high affinity to both midkine and pleiotrophin and harbors chondroitin sulfate chains. Furthermore, strong synergism between midkine and platelet-derived growth factor in migration was detected. The use of specific inhibitors demonstrated that mitogen-activated protein (MAP) kinase and protein-tyrosine phosphatase were involved in midkine-induced haptotaxis but not PDGF-induced chemotaxis, whereas phosphatidylinositol 3 (PI3)-kinase and protein kinase C were involved in both functions. Midkine activated both PI3-kinase and MAP kinases, the latter activation was blocked by a PI3-kinase inhibitor. Midkine further recruited PTPzeta and PI3-kinase. These results indicate that PTPzeta and concerted signaling involving PI3-kinase and MAP kinase are required for midkine-induced migration and demonstrate for the first time the synergism between midkine and platelet-derived growth factor in cell migration.
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PMID:Haptotactic migration induced by midkine. Involvement of protein-tyrosine phosphatase zeta. Mitogen-activated protein kinase, and phosphatidylinositol 3-kinase. 1134 82

Normal prostate expresses the receptor protein-tyrosine phosphatase, PTPmu, whereas LNCaP prostate carcinoma cells do not. PTPmu has been shown previously to interact with the E-cadherin complex. LNCaP cells express normal levels of E-cadherin and catenins but do not mediate either PTPmu- or E-cadherin-dependent adhesion. Re-expression of PTPmu restored cell adhesion to PTPmu and to E-cadherin. A mutant form of PTPmu that is catalytically inactive was re-expressed, and it also restored adhesion to PTPmu and to E-cadherin. Expression of PTPmu-extra (which lacks most of the cytoplasmic domain) induced adhesion to PTPmu but not to E-cadherin, demonstrating a requirement for the presence of the intracellular domains of PTPmu to restore E-cadherin-mediated adhesion. We previously observed a direct interaction between the intracellular domain of PTPmu and RACK1, a receptor for activated protein kinase C (PKC). We demonstrate that RACK1 binds to both the catalytically active and inactive mutant form of PTPmu. In addition, we determined that RACK1 binds to the PKCdelta isoform in LNCaP cells. We tested whether PKC could be playing a role in the ability of PTPmu to restore E-cadherin-dependent adhesion. Activation of PKC reversed the adhesion of PTPmuWT-expressing cells to E-cadherin, whereas treatment of parental LNCaP cells with a PKCdelta-specific inhibitor induced adhesion to E-cadherin. Together, these studies suggest that PTPmu regulates the PKC pathway to restore E-cadherin-dependent adhesion via its interaction with RACK1.
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PMID:Expression of the receptor protein-tyrosine phosphatase, PTPmu, restores E-cadherin-dependent adhesion in human prostate carcinoma cells. 1180 4

During mitosis, the catalytic activity of protein-tyrosine phosphatase (PTP) alpha is enhanced, and its inhibitory binding to Grb2, which specifically blocks Src dephosphorylation, is decreased. These effects act synergistically to activate Src in mitosis. We show here that these effects are abrogated by mutation of Ser180 and/or Ser204, the sites of protein kinase C-mediated phosphorylation within PTPalpha. Moreover, either a Ser-to-Ala substitution or serine dephosphorylation specifically eliminated the ability of PTPalpha to dephosphorylate and activate Src even during interphase. This explains why the substitutions eliminated PTPalpha transforming activity, even though PTPalpha interphase dephosphorylation of nonspecific substrates was only slightly decreased. This occurred without change in the phosphorylation of PTPalpha at Tyr789, which is required for "phosphotyrosine displacement" during Src dephosphorylation. Thus, in addition to increasing PTPalpha nonspecific catalytic activity, Ser180 and Ser204 phosphorylation (along with Tyr789 phosphorylation) regulates PTPalpha substrate specificity. This involves serine phosphorylation-dependent differential modulation of the affinity of Tyr(P)789 for the Src and Grb2 SH2 domains. The results suggest that protein kinase C may participate in the mitotic activation of PTPalpha and Src and that there are intramolecular interactions between the PTPalpha C-terminal and membrane-proximal regions that are regulated, at least in part, by serine phosphorylation.
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PMID:Mitotic activation of protein-tyrosine phosphatase alpha and regulation of its Src-mediated transforming activity by its sites of protein kinase C phosphorylation. 1192 5

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

We investigated the specificity for gram-negative stimuli as well as the contribution of signal transduction pathways for leukocyte hyporesponsiveness in sepsis or following cardiopulmonary bypass (CPB). Whole blood of nine patients undergoing CPB and 25 patients with severe sepsis was stimulated ex vivo with LPS (E. coli O111:B4) or with Staphylococcus aureus Cowan strain I (SAC-I) lysate in the absence or presence of inhibitors of protein kinase C (PKC), protein-tyrosine kinase (PTK), or protein-tyrosine phosphatase (PTP). Both toxins stimulated a TNF-alpha response through PTK signaling. Although suppression of the cytokine response was similar for LPS and SAC-I after CPB, it was significantly more pronounced for SAC-I in sepsis. Inhibition of PTP failed to increase TNF-alpha upon LPS, whereas a moderate increase was observed with SAC-I. Impaired TNF-alpha responses occur in sepsis and after CPB. Although this has primarily been reported for gram-negative stimuli, our data suggest that this is even more pronounced for gram-positive stimuli in severe sepsis. Although PTK was the predominant signaling pathway, inhibition of PTP only partially restored the TNF-alpha response to SAC-I. Our results suggest that cellular mechanisms underlying monocyte deactivation are different in sepsis or following CPB and are discriminate for gram-positive and gram-negative toxins.
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PMID:Monocyte deactivation in severe human sepsis or following cardiopulmonary bypass. 1202 53

Serine phosphorylation of the ShcA signaling molecule has been reported recently. In this work, we have identified 12-O-tetradecanoylphorbol-13-acetate (TPA)- and growth factor-induced serine/threonine phosphorylation sites in p52(Shc) and p66(Shc). Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms. Insulin also induced ShcA/PTP-PEST association, although to a lesser extent than TPA. Overexpression of a PTP-PEST binding-defective mutant of p52(Shc) (S29A) enhanced insulin-induced ERK activation in insulin receptor-overexpressing HIRc-B cells. Consistent with this, p52(Shc) S29A was more tyrosine-phosphorylated than wild-type p52(Shc) after insulin stimulation. Thus, we have identified a new mechanism whereby serine phosphorylation of ShcA controls the ability of its phosphotyrosine-binding domain to bind PTP-PEST, which is responsible for the dephosphorylation and down-regulation of ShcA after insulin stimulation.
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PMID:Serine/threonine phosphorylation of ShcA. Regulation of protein-tyrosine phosphatase-pest binding and involvement in insulin signaling. 1205 29

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