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)

Phosphorylation of CD45, a transmembrane protein-tyrosine phosphatase (PTPase), has been proposed to mediate docking of signaling proteins and to modulate PTPase activity. To study the role of phosphorylation in CD45, in vivo phosphorylation sites of CD45 from 70Z/3.12 cells were identified using 32P labeling, trypsin digestion, two-dimensional peptide mapping, high performance liquid chromatography, phosphoamino acid analysis, matrix-assisted laser desorption/ionization mass spectrometry, and specific enzymatic degradation. Eight phosphopeptides, a through h, were isolated and four phosphorylation sites were identified. All four phosphorylation sites were in the membrane-distal PTPase domain (D2) and the C-terminal tail and none were in the membrane-proximal PTPase domain (D1). One site, Ser(P)939 peptide h, was in the D2 domain and, by comparison to the three-dimensional structure of PTP1B, is predicted to lie at the apex of the substrate binding loop. Ser939 was the only in vitro phosphorylation site for protein kinase C among the phosphorylation sites identified. Four of the C-terminal peptides identified (d, e, f, and g) spanned the same sequence and were derived from the same phosphorylation site in the C-terminal tail, Ser1204. Peptide a was derived from the intact C terminus and comprised a mixture of monophosphorylated peptides containing either Ser(P)1248 or Thr(P)1246. Knowledge of the precise phosphorylation sites of CD45 will lead to the design of experiments to define the role of phosphorylation in PTPase activity and in signaling.
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PMID:Identification of in vivo phosphorylation sites of CD45 protein-tyrosine phosphatase in 70Z/3.12 cells. 911 Oct 75

The amyloid precursor protein (APP) of Alzheimer's disease is a transmembrane protein that is cleaved by an uncharacterized enzyme known as alpha-secretase within its extracellular/intraluminal domain after the activation of guanine nucleotide-binding protein-coupled receptors linked to phosphoinositide hydrolysis. The secretory process results in the release of large soluble derivatives of APP (APPs), and, when elicited by muscarinic receptor activation, exhibits both protein kinase C (PKC)-dependent and tyrosine phosphorylation-dependent components [Slack, Breu, Petryniak, Srivastava and Wurtman (1995) J. Biol. Chem. 270, 8337-8344]. In this report we examine the regulation of the release of APPs by epidermal growth factor (EGF) receptors, which possess intrinsic tyrosine kinase activity, and are coupled to a variety of effectors including phosphoinositide-specific phospholipase Cgamma. In A431 cells, EGF caused time-dependent and dose-dependent increases in the formation of inositol phosphates in cultures prelabelled with myo--3H-inositol, and in the release of APPs into the culture medium; the two responses exhibited similar time courses and EC50 values for EGF. Concomitant with these effects, there were concentration-dependent (3-300 ng/ml) increases in the phosphorylation of tyrosine residues in several proteins, including the EGF receptor itself. The specific PKC antagonist GF 109203X decreased the effect of EGF by approx. 35% at a concentration that abolished the stimulation of the release of APPs by the PKC activator PMA. Tyrphostin AG 1478, an inhibitor of EGF receptor tyrosine kinase, abolished the EGF-induced release of APPs. These results demonstrate that in A431 cells, activation of the EGF receptor stimulates alpha-secretase activity by a mechanism that is partly dependent on PKC activity.
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PMID:Rapid stimulation of amyloid precursor protein release by epidermal growth factor: role of protein kinase C. 935 59

Polarized epithelial cells separate two extremely different cellular milieus. The tight junction (TJ) is the most apical component of the junctional complex and serves as the permeability barrier between these environments. The tight junctional complex appears to be a dynamic and regulated structure. Some of its protein components have been identified and include the transmembrane protein occludin. Nontransmembrane proteins on the cytosolic leaflet including ZO-1, ZO-2, cingulin, 7H6, and several unidentified phosphoproteins are also believed to be part of the TJ. Interactions of some of these proteins with the actin cytoskeleton are a major determinant of TJ structure and may also play a role in the regulation of TJ assembly. Recent progress using the "calcium switch" and the "ATP depletion-repletion" model of TJ formation offers new insight regarding how these structures form. TJ biogenesis appears to be regulated, in part, by classic signal transduction pathways involving heterotrimeric G proteins, release of intracellular Ca2+, and activation of protein kinase C. Although many of the details of the signaling pathways have yet to be defined, these observations may provide insight into how TJs form during tubular development. Furthermore, it may be possible to suggest potential therapeutic targets for intervention in a variety of diseases (e.g., ischemia, toxic injury to the kidney and other epithelial tissue) where TJ integrity has been compromised and reassembly is required.
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PMID:Molecular structure and assembly of the tight junction. 945 17

The transmembrane protein tissue factor (TF) is the cell surface receptor for coagulation factor VII (FVII) and activated factor VII (FVIIa). Recently, TF has been identified as a regulator of angiogenesis, tumor growth, and metastasis. This study was designed to link the binding of FVII(a) to its receptor, TF, with the subsequent triggering of angiogenesis through vascular endothelial growth factor (VEGF) production by human lung fibroblasts. We report that incubation of fibroblasts, which express constitutive surface TF, with FVII(a) induces VEGF synthesis. FVII(a)-induced VEGF secretion, assessed by a specific enzyme-linked immunosorbent assay, was time- and concentration-dependent. VEGF secretion was maximal after 24 hours of incubation of the cells with 100 nmol/L FVII(a) and represented a threefold induction of the basal VEGF level. Reverse transcriptase-polymerase chain reaction analysis of VEGF detected three mRNA species of 180, 312, and 384 bp corresponding, respectively, to VEGF121, VEGF165, and VEGF189. A 2.5- to 3.5-fold increase was observed for the 180- and 312-bp transcripts at 12 and 24 hours, respectively. FVII(a)-dependent VEGF production was inhibited by a pool of antibodies against TF, pointing to the involvement of this receptor. On specific active-site inhibition with dansyl-glutamyl-glycinyl-arginyl chloromethyl ketone, FVIIa lost 70% of its capacity to elicit VEGF production. Consistent with this, the native form (zymogen) of FVII only had a 1.8-fold stimulating effect. Protein tyrosine kinase and protein kinase C are involved in signal transduction leading to VEGF production, as shown by the inhibitory effects of genistein and GF 109203X. The results of this study indicate that TF is essential for VIIa-induced VEGF production by human fibroblasts and that its role is mainly linked to the proteolytic activity of the TF-VIIa complex.
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PMID:Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII. 953 78

The tight junction creates a regulated barrier in the paracellular pathway and, together with the actin-rich adherens junction, forms a functional unit called the apical junction complex. A growing number of tight junction-associated proteins have been identified, but functions are defined for only a few. The intercellular barrier is formed by rows of the transmembrane protein occludin, which is bound on the cytoplasmic surface to ZO-1 and ZO-2. These proteins are members of the membrane-associated guanylate kinase (MAGUK) protein family and are likely to have both structural and signaling roles. Junctional plaque proteins without known functions include cingulin, p130, and 7H6; single reports describe ZA-1TJ and symplekin. Many cellular signaling pathways affect assembly and sealing of junctions. Transducing proteins, which localize within the junction, include both heterotrimeric and rho-related GTP-binding proteins, PKC-zeta and nonreceptor tyrosine kinases. Control of perijunctional actin may be the unifying mechanism for regulating paracellular permeability.
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PMID:Molecular architecture of tight junctions. 955 57

HIV-1 uses CD4 and chemokine receptors as cofactors for cellular entry. The viral envelope transmembrane protein gp41 is thought to participate in viral fusion with CD4(+) cells. We investigated whether gp41 interacts with chemokine receptors on human monocytes by testing its effect on the capacity of cells to respond to chemokine stimulation. Monocytes preincubated with gp41 of the MN strain showed markedly reduced binding, calcium mobilization, and chemotaxis in response to a variety of chemokines as well as to the bacterial peptide fMLP. This generalized inhibition of monocyte activation by chemoattractants required the presence of CD4, since the effect of gp41 was only observed in CD4(+) monocytes and in HEK293 cells cotransfected with chemokine receptors and an intact CD4, but not a CD4 lacking its cytoplasmic domain. Confocal microscopy showed that gp41 caused internalization of CXCR4 in HEK293 cells provided they were also cotransfected with intact CD4. In addition, pretreatment of monocytes with protein kinase C inhibitors partially reversed the inhibitory effect of gp41. Thus, gp41, which had not previously been implicated as interacting with HIV-1 fusion cofactors, downregulates chemoattractant receptors on monocytes by a CD4-dependent pathway.
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PMID:HIV-1 envelope gp41 is a potent inhibitor of chemoattractant receptor expression and function in monocytes. 971 Apr 49

Fas (CD95/APO-1) is a transmembrane protein of the TNF/neuron growth factor receptor family. Ligation of Fas by specific Abs or Fas ligand (FasL/CD95 ligand) induces rapid apoptotic cell death in a variety of cell types. Despite progress in understanding the death signals transduced from Fas, very little is known with regard to the mechanisms by which Fas expression is regulated. Using our previously established murine T cell hybridoma model A1.1, we show that specific protein kinase C (PKC) inhibitors could block activation-induced Fas expression and apoptosis. The activation of PKC with PMA or 1-oleoyl-2-acetyl-sn-glycerol could mimic the TCR signal by inducing the expression of Fas but not FasL. PKC-dependent Fas expression was also observed in several murine and human tumor cell lines. Since the inhibition of Ca2+ redistribution by an inhibitor of intracellular Ca2+ mobilization, 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride, inhibited TCR-induced FasL but not Fas, the expression of Fas appears to be independent of Ca2+ mobilization. Significantly, expression of the newly identified Fas-regulatory gene, TDAG51, was found to be dependent upon the activity of PKC. PKC activation only induced Fas expression in cells expressing wild-type TDAG51. Thus, Fas expression is likely mediated by PKC through TDAG51.
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PMID:Protein kinase C regulates Fas (CD95/APO-1) expression. 972 12

Growth factors and their receptors are known to play important roles in normal cell proliferation, tissue repair, and ulcer healing. Epidermal growth factor (EGF) inhibits acid secretion, protects gastric mucosa against injury, mediates mucosal adaptation, and accelerates gastroduodenal ulcer healing. EGF exerts its actions by binding to its receptor (EGF-R), which is a transmembrane protein tyrosine kinase. Binding of EGF to its receptor triggers receptor dimerization and autophosphorylation, recruitment of kinase substrates (signaling enzyme adapter proteins with an SH2 domain, Grb2 adapter protein, and Grb2-SOS complex). These events lead to Ras (GTP-binding protein) phosphorylation and activation of the Ras/Raf/MAP kinase pathway, in turn leading to phosphorylation of regulatory proteins and transcription factors and culminating in cell proliferation. Other pathways potentially activated by EGF include the phosphatidylinositol pathway (leading to activation of protein kinase C and an increase in cytosolic calcium) and the JAK/STAT signaling pathway. While EGF-induced signaling events have been extensively studied in various cell systems, predominantly neoplastic and/or transformed cells, the relevance of those findings to gastric mucosal injury repair or ulcer healing is as yet not fully elucidated. This paper is intended to provide an overview of signaling pathways triggered by EGF-R activation and on this background to summarize current knowledge pertaining to involvement of EGF-R signaling pathways in gastric mucosal repair and ulcer healing.
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PMID:Signal transduction cascades triggered by EGF receptor activation: relevance to gastric injury repair and ulcer healing. 975 21

The glucocorticoid-inducible transmembrane protein CD163 is a member of the scavenger receptor cysteine-rich (SRCR) family which is expressed exclusively on human monocytes and macrophages. The expression of the protein is significantly downregulated in response to phorbol 12-myristate 13-acetate (PMA) by a yet unknown mechanism. We now demonstrate that PMA induces shedding of a soluble form of CD163 rather than internalization, revealing a novel regulatory mechanism for a member of the SRCR family. Bisindolylmaleimide I was shown to inhibit phorbol ester-induced shedding, thus implying an involvement of protein kinase C (PKC). Furthermore, cleavage could be prevented by protease inhibitors. Therefore, we suggest that PMA-induced activation of PKC leads to protease-mediated shedding of CD163. These results indicate a specific release mechanism of soluble CD163 by human monocytes which could play an important role in modulating inflammatory processes.
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PMID:Shedding of CD163, a novel regulatory mechanism for a member of the scavenger receptor cysteine-rich family. 1006 32

Down-regulation of the T-cell receptor (TCR) plays an important role in modulating T-cell responses, both during T-cell development and in mature T cells. At least two distinct pathways exist for TCR down-regulation: down-regulation following TCR ligation; and down-regulation following activation of protein kinase C (PKC). Ligand-induced TCR down-regulation is dependent on protein tyrosine kinase (PTK) activity and seems to be closely related to T-cell activation. In addition, previous studies have indicated that ligand-induced TCR down-regulation is dependent on the expression of CD45, a transmembrane protein tyrosine phosphatase. The role of the different domains of CD45 in TCR down-regulation was investigated in this study. We found that the phosphatase domains of CD45 are required for efficient ligand-induced TCR down-regulation. In contrast, the extracellular domain of CD45 is dispensable for ligand-mediated TCR down-regulation. Finally, PKC-mediated TCR down-regulation was found to be independent of both the extra-and intracellular domains of CD45.
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PMID:The phosphatase domains of CD45 are required for ligand induced T-cell receptor downregulation. 1079 41


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