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)

Human alpha-thrombin and histamine each stimulates protein phosphorylation in human umbilical vein endothelial cells (HUVEC). We have identified the most prominent of these phosphoproteins by immunoprecipitation as the human homolog of the widely distributed myristoylated alanine-rich C-kinase substrate (MARCKS). Stimulation by 0.1-10 U/ml of alpha-thrombin produces a time-dependent, sustained (plateau 3-5 min) level of MARCKS phosphorylation. MARCKS phosphorylation requires thrombin catalytic activity but not receptor binding and is also seen in response to stimulation by a peptide, TR (42-55), that duplicates a portion of the thrombin receptor tethered ligand created by thrombin proteolytic activity. One micromolar histamine, like alpha-thrombin, produces sustained phosphorylation of MARCKS (plateau 3-5 min). In contrast, 100 microM histamine results in rapid but transient MARCKS phosphorylation (peak 1-3 min). HUVEC treated with 100 microM histamine for 5 min can be restimulated by alpha-thrombin but not fresh histamine, suggesting that the histamine receptor was desensitized. MARCKS phosphorylation can also be induced by several exogenous protein kinase C (PKC) activators and both alpha-thrombin- and histamine-induced MARCKS phosphorylation are inhibited by the PKC antagonist staurosporine. However, while prolonged PMA pretreatment ablates histamine-induced MARCKS phosphorylation, the ability of thrombin to induce MARCKS phosphorylation is retained. These findings provide evidence for agonist-specific pathways of protein kinase activation in response to thrombin and histamine in HUVEC.
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PMID:Thrombin and histamine rapidly stimulate the phosphorylation of the myristoylated alanine-rich C-kinase substrate in human umbilical vein endothelial cells: evidence for distinct patterns of protein kinase activation. 132 36

We have isolated and sequenced complementary DNA (cDNA) for the human 80K-L protein, a major substrate for protein kinase C and the human homologue of an 80- to 87-kDa bovine protein named MARCKS (myristoylated alanine-rich C kinase substrate). The human 80K-L cDNA encodes a protein of 332 amino acids with a calculated molecular weight of 31,534. Homology comparisons of the nucleotide sequences of the cDNAs indicated that their 3'-untranslated regions are more homologous than the coding regions. Spot blot hybridization using flow-sorted human chromosomes indicated that the gene encoding the 80K-L protein, designated MACS, maps to the q15----qter region of human chromosome 6, and it also suggested that a genomic region with a sequence homologous to the 3'-untranslated region of the 80K-L mRNA exists on chromosome 21.
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PMID:Molecular cloning and chromosomal mapping of a cDNA encoding human 80K-L protein: major substrate for protein kinase C. 142 23

A major in vivo substrate of Ca(2+)-phospholipid-dependent protein kinase (myristoylated alanine-rich C-kinase substrate (MARCKS)) has been purified to apparent homogeneity from the particulate as well as from the cytoplasmic fractions of calf brain using a calmodulin affinity column. The two preparations were characterized and compared with various biochemical and biophysical techniques. Although they behave similarly in various chromatographic procedures during purification, their elution positions from the gel filtration column are markedly different. Stokes radii of 85 and 45 A were measured for the cytoplasmic and membrane MARCKS, respectively. Once purified, however, they show a similar small Stokes radius (45 A), suggesting the dissociation of a component or a drastic conformational change in the cytoplasmic preparation during purification. The electrospray mass spectroscopic analysis of the two preparations revealed the existence of at least three major subpopulations with molecular mass differences of 80 daltons, which suggests the presence of protein phosphorylated in different degrees. The cytoplasmic preparation contains more phosphorylated species compared with the membrane preparation, whereas the calculated molecular weight of each peak was indistinguishable between the two preparations. Correspondingly, when the two preparations were phosphorylated by purified protein kinase C in vitro, more phosphate groups were transferred to the membrane preparation (4 mol/mol) than to the cytoplasmic preparation (2.9 mol/mol). A significant difference was also observed in the inhibition of calmodulin of the phosphorylation reaction. On the other hand, the circular dichroism of the two preparations showed similar spectra rich in random coil with little contribution of alpha-helix (approximately 10%), suggesting that there is not a significant difference in the overall conformation. These results clearly established that the two preparations are the same protein coded by a single gene but they differ in their degree of phosphorylation, and that the difference observed in their Stokes radius is due to the presence of an unidentified factor that is removed from the cytoplasmic MARCKS during purification.
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PMID:Affinity purification and characterization of myristoylated alanine-rich protein kinase C substrate (MARCKS) from bovine brain. Comparison of the cytoplasmic and the membrane-bound forms. 142 82

A polyclonal antiserum raised against an oligopeptide with an amino acid sequence corresponding to a sequence of the myristoylated alanine-rich C-kinase substrate (MARCKS) from mouse macrophages and rat brain recognizes the 80-kDa C-kinase substrate from Swiss 3T3 fibroblasts. Using this antiserum for quantitative determination of the 80-kDa MARCKS-related protein, we found that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induces a rapid down-regulation of this protein in the fibroblasts. In accordance with earlier reports, TPA causes phosphorylation of the 80-kDa protein which can be inhibited by staurosporine. Staurosporine also suppresses the TPA-induced down-regulation, possibly indicating that the down-regulation of the MARCKS-related protein is dependent on its phosphorylation by protein kinase C.
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PMID:Phorbol ester-induced down-regulation of the 80-kDa myristoylated alanine-rich C-kinase substrate-related protein in Swiss 3T3 fibroblasts. Inhibition by staurosporine. 173 May 92

We have recently reported a potent mitogenic stimulation of oligodendroglial (OL) progenitors by the protein kinase C (PKC) activating phorbol ester, i.e., phorbol 12-myristate 13-acetate (PMA) (Bhat NR, J Neurosci Res 22:20-27, 1989). The present study deals with PMA-induced protein phosphorylation reactions in cultured OL progenitors. The phorbol ester induced the phosphorylation of several cytosol and membrane-associated proteins, including a major protein with an apparent molecular weight of 80 kDa. In both control and PMA-treated cultures, phosphorylation level of the 80-kDa protein in cytosol was higher than that in the particulate fraction. Okadaic acid, an inhibitor of protein phosphatases, also increased the phosphorylation of several proteins and substantially enhanced protein phosphorylation induced by PMA. In vitro incubation of the cell membranes with phosphatidylserine and diacylglycerol (a physiological activator of PKC) in the presence of [gamma 32p]-ATP resulted in an increased phosphorylation of the 80-kDa protein. The induction of phosphorylation of the 80-kDa protein under both in situ and in vitro conditions was subject to inhibition by 1-[5[isoquinolinyl sulfonyl)-3-methylpiperazine (H-7), a potent inhibitor of PKC. The 80-kDa phosphoprotein was identified as the prominent PKC substrate, i.e., myristoylated alanine-rich C-kinase substrate (MARCKS) protein by immunoprecipitation with anti-MARCKS antibodies.
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PMID:Phosphorylation of MARCKS (80-kDa) protein, a major substrate for protein kinase C in oligodendroglial progenitors. 179 60

We have isolated a mouse brain cDNA clone encoding a protein of 200 amino acids (Mr 20,165) with partial homology with MARCKS (myristoylated alanine-rich C-kinase substrate). Two regions show similarity with MARCKS, one is the kinase C phosphorylation site domain which is supposed to bind calmodulin, and the other is the region near to the N-terminus, including the consensus sequence of myristoylation. It has a similar amino acid composition to MARCKS, but the content of alanine is not as high. It is distributed throughout the mouse brain, but the pattern is not identical with that of MARCKS. Both proteins may be members of a new protein family involved in coupling the protein kinase C and calmodulin signal transduction systems.
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PMID:A mouse brain cDNA encodes a novel protein with the protein kinase C phosphorylation site domain common to MARCKS. 186 62

A Mr-80,000 acidic phosphoprotein ('80K protein') is a specific substrate for protein kinase C. We attempted to purify the 80K protein from a human squamous-cell carcinoma cell line, Ca9-22, by the sequential use of heat treatment, (NH4)2SO4 precipitation, Mono Q column chromatography, proRPC column chromatography and gel filtration. The 80K protein was assayed by phosphorylation in vitro by using partially purified human type III protein kinase C, and was fractionated into two distinct molecular species with slightly different Mr values, designated 80K-L and 80K-H proteins. Phosphorylation occurred mainly at serine residues of these proteins. Two-dimensional phosphopeptide maps after trypsin digestion and kinetic profiles of phosphorylation were different from each other. Ca2(+)- and phospholipid-dependency of the phosphorylation in vitro confirmed that both 80K-L and 80K-H proteins are true substrates for three subtypes of protein kinase C. The 80K-L protein was a preferential substrate for type III protein kinase C, and the 80K-H protein was phosphorylated more effectively by type I and type II protein kinase C. The possible roles of these two distinct 80K proteins in signal transduction are discussed.
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PMID:Purification of two distinct proteins of approximate Mr 80,000 from human epithelial cells and identification as proper substrates for protein kinase C. 224 94

Protein phosphorylation induced by endothelins has been studied using [32P]orthophosphate-prelabelled rat cerebellar slices. Endothelin-1 increased phosphorylation of an 87 kDa protein in a time-dependent manner (reaching a maximum effect at about 2.5 min) and with an EC50 equal to 93 +/- 32 nM. Endothelin-3 and sarafotoxin 6c induced similar levels of phosphorylation. Endothelin-1 also promoted [3H]inositol phosphate accumulation with similar EC50 (71 +/- 7.5 nM). The phosphoprotein of 87 kDa seems to be myristoylated alanine-rich C-kinase substrate (MARCKS) as demonstrated by acetic acid extraction. In addition, 12-O-tetradecanoylphorbol-13-acetate (TPA) increased 87 kDa protein phosphorylation while Ro-31-8220, a specific protein kinase inhibitor, inhibited both TPA and endothelin-induced 87 kDa protein phosphorylation. Therefore, it is concluded that protein kinase C is involved in the endothelin action on cerebellum.
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PMID:Endothelin-1 stimulates myristoylated alanine-rich C-kinase substrate (MARCKS) phosphorylation in rat cerebellar slices. 747 12

gp39 is expressed on anti-CD3-activated Th, and binds CD40 on the B cell, driving B cell cycle entry. In this study, the signal-transduction pathway initiated in B cells as a consequence of interacting with activated Th is examined. Unlike anti-membrane Ig (anti-mlg) or anti-MHC class II, plasma membranes (PM) isolated from anti-CD3-activated Th, PMAct did not trigger an increase in the B cell intracellular concentrations of cAMP or calcium. In addition, PMAct did not stimulate protein kinase C activation as measured by myristoylated alanine-rich C-kinase substrate (MARCKS) phosphorylation and protein kinase C translocation. The failure to detect these biochemical events may be caused by the asynchrony with which PMAct induce these normally transient biochemical changes. Alternatively, PMAct may not trigger these events. PMAct did induce the tyrosine phosphorylation of several B cell substrates. Neutralizing Abs directed against gp39 inhibited PMAct-induced protein tyrosine phosphorylation of B cell substrates. These results suggest that cognate interactions in B cells initiate a signal-transduction pathway that is different from the pathway initiated by cross-linking of mlg or MHC class II.
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PMID:Signaling events during helper T cell-dependent B cell activation. I. Analysis of the signal transduction pathways triggered by activated helper T cell in resting B cells. 751 24

Phorbolester-triggered differentiation of SH-SY5Y neuroblastoma cells requires serum and a prolonged activation of protein kinase C (PKC). Under serum-free conditions development of a mature phenotype requires phorbolester in combination with a member of either the insulin-like growth factor (IGF) or the platelet-derived growth factor family. Here we report that basic and acidic fibroblast growth factor (FGF) and epidermal growth factor, but not nerve growth factor, synergistically potentiate phorbolester-induced differentiation. Alone these factors induced a mitogenic response which varied in magnitude, with basic FGF and IGF-I being the two most potent mitogens. However, a combination of basic FGF and IGF-I induced differentiation as judged by morphology and the increase in growth associated protein (GAP-43) and neuropeptide tyrosine mRNA levels. In contrast to the phenotype obtained in the presence of phorbolester, bFGF and IGF-I-treated SH-SY5Y cells retained their capacity to proliferate. Finally, in these cells, the phosphorylation of the endogenous PKC substrate, myristoylated alanine-rich C-kinase substrate (MARCKS), was slightly increased during several days, suggesting an involvement of PKC in the bFGF and IGF-I-induced differentiation.
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PMID:Basic FGF and IGF-I promote differentiation of human SH-SY5Y neuroblastoma cells in culture. 751 11


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