Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies [Summercorn et al. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 8834-8838; Klarlung & Czech (1988) J. Biol. Chem. 263, 15872-15875] have indicated that Balb/c 3T3 cells and 3T3-L1 adipocytes incubated with insulin show increased casein kinase II activity within minutes, implicating this serine/threonine kinase as an early step in an insulin signaling pathway. We recently reported the isolation of a cDNA encoding an alpha subunit of human casein kinase II [Meisner et al. (1989) Biochemistry 28, 4072-4076] as an initial step toward examining the regulation of this enzyme. We now describe a HepG2 cell casein kinase II beta subunit cDNA of 2.57 kb containing 96 bases of 5' untranslated sequence, 645 bases of open reading frame, and 1832 bases of 3' untranslated sequence with two polyadenylation consensus signal sequences and two poly(A) stretches. The open reading frame of the human beta subunit cDNA was 77% and 87% identical with the Drosophila sequence at the nucleotide and amino acid levels, respectively, and 99% identical with the bovine amino acid sequence. RNA analysis of HepG2 cell RNA utilizing HepG2 beta subunit cDNA fragments as probes revealed one major band migrating at 1.2 kb and two minor bands migrating at 3.0 and 4.2 kb. Results from DNA analysis of HepG2 genomic DNA, consistent with results utilizing Drosophila genomic DNA, suggest the presence of a single gene for the beta subunit of casein kinase II.
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PMID:Cloning and characterization of a cDNA encoding the beta subunit of human casein kinase II. 251 84

Chymotryptic digestion was used to localize the sites in microtubule-associated protein 2 which are preferentially phosphorylated in vitro by MAP kinase, an insulin-stimulated serine/threonine kinase which efficiently utilizes high molecular weight MAPs as substrates. MAP kinase phosphorylates sites in the projection domain almost exclusively; less than 6% of the phosphate incorporated by MAP kinase was found in the tubulin binding domain. This site specificity is in marked contrast to that of the catalytic subunit of cAMP dependent protein kinase, and most other protein kinases phosphorylating MAP-2, which extensively phosphorylate the tubulin binding domain.
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PMID:Phosphorylation of microtubule-associated protein 2 by MAP kinase primarily involves the projection domain. 254 2

pp42, a low-abundance 42-kDa protein, becomes transiently phosphorylated on tyrosine after stimulation of fibroblasts by a variety of mitogens, including epidermal growth factor, platelet-derived growth factor, phorbol 12-myristate 13-acetate, thrombin, and insulin-like growth factor II. The induction of pp42 phosphorylation on tyrosine by such diverse mitogenic agents suggests an important role for pp42 in the cascade of events necessary for cell transition from G0 into the cell cycle. However, as with most proteins identified on the basis of their tyrosine phosphorylation, the function of pp42 in cellular regulation is unknown. In this manuscript we report evidence that suggests that pp42 is a serine/threonine-specific protein kinase. Stimulation of 3T3-L1 cells with insulin has been shown to activate a cytosolic serine/threonine kinase capable of phosphorylating microtubule-associated protein 2 (MAP-2) and ribosomal protein S6 kinase II. This cytosolic serine/threonine protein kinase, which itself is phosphorylated on tyrosine, has been termed "MAP kinase". We now report that pp42 phosphorylation and MAP kinase activation occur in fibroblasts in response to similar mitogens, that the two proteins comigrate on one- and two-dimensional polyacrylamide gels, and that the two proteins copurify chromatographically. The major peptides generated from purified MAP kinase by V8 protease digestion are present as a subset of the peptides in digests of pp42 excised from two-dimensional gels. Thus, the results suggest that MAP kinase is tyrosine-phosphorylated pp42.
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PMID:Evidence that pp42, a major tyrosine kinase target protein, is a mitogen-activated serine/threonine protein kinase. 255 Sep 26

Addition of cAMP to various cultured cell types has a dramatic effect on cell growth. Both positive and negative effects on growth have been demonstrated. Analysis of mutants with altered cAMP dependent protein kinases suggests that tumour cells do not require a functional endogenous cAMP system for normal cell cycling. Whether or not cAMP stimulates or inhibits cell growth depends on the cell type, the oncogene driving its growth, the dose of cAMP and the environment of the cell. The ras gene product does not appear to be a component of the adenylate cyclase system, and no other oncogenes have been shown to use cAMP as a second messenger. However, another class of oncogenes possesses a serine/threonine kinase activity analogous to that of cAMP dependent protein kinase. Several oncogene products and growth factor receptors are phosphorylated on serine residues, suggesting that some oncogene products, such as pp60src may be targets for the action of cAMP. The role of cAMP in tumour cell growth may be to modulate the activity of the oncogenes or their protein targets which control cell growth.
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PMID:The role of cAMP in regulating tumour cell growth. 302 24

We have examined the phosphorylation and the serine/threonine-specific kinase activity of the protooncogene product Raf-1 (formerly c-raf) in response to oncogenic transformation or growth-factor treatment of mouse 3T3 cells. Expression of the membrane-bound oncogene products encoded by v-fms, v-src, v-sis, polyoma virus middle-sized tumor antigen, and Ha-ras increased the apparent molecular weight and phosphorylation of the Raf-1 protein, while expression of the nuclear oncogene and protooncogene products encoded by v-fos and c-myc did not. Changes in electrophoretic mobility and phosphorylation occurred rapidly in response to treatment of cells with platelet-derived growth factor, acidic fibroblast growth factor, epidermal growth factor, and the protein kinase C activator phorbol 12-myristate 13-acetate, but not insulin. The phosphorylation of the Raf-1 protein occurred primarily on serine and threonine residues. However, a subpopulation of Raf-1 molecules was phosphorylated on tyrosine residues in cells transformed by v-src or stimulated with platelet-derived growth factor. Transformation by v-src, or treatment with platelet-derived growth factor or phorbol 12-myristate 13-acetate, activated the Raf-1-associated serine/kinase activity as measured in immune-complex kinase assays. These findings suggest that proliferative signals generated at the membrane result in the phosphorylation of the Raf-1 protein and the activation of its serine/threonine kinase activity. Raf-1 activation may thus serve to transduce signals from the membrane to the cytoplasm and perhaps on to the nucleus.
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PMID:Signal transduction from membrane to cytoplasm: growth factors and membrane-bound oncogene products increase Raf-1 phosphorylation and associated protein kinase activity. 305 94

The inhibitory potencies of bioflavonoids on various tyrosine protein kinases and serine/threonine protein kinases were investigated. The phosphotransferase activity of an oncogene product, pp130fps, and a growth factor receptor, insulin receptor, were inhibited by myricetin, a derivative of quercetin. However, tyrosine kinase activity in the particulate fraction from human platelets (PM-TPK) was resistant to myricetin. Apparent Ki values of myricetin for tyrosine protein kinases of pp130fps and insulin receptor were 1.8 and 2.6 microM, respectively. The Ki values for serine/threonine kinase activities of myosin light chain kinase (MLC-kinase), casein kinase I, casein kinase II, cAMP-dependent protein kinase, and protein kinase C were 1.7 microM, 9.0 microM, 0.6 microM, 27.5 microM, and 12.1 microM, respectively. Lineweaver-Burk plots revealed that myricetin competitively inhibits pp130fps tyrosine kinase, myosin light chain kinase, casein kinase I and II with ATP, but does not inhibit other protein kinases. Since myricetin is a hydroxylated derivative of quercetin, the inhibitory effects of a series of seven flavonoids with various numbers of hydroxy residues were examined. Structure activity studies exhibited that the inhibitory potencies of the flavonoids for tyrosine kinases of pp130fps and insulin receptor correlated with the number of hydroxy residues on the flavone rings (gamma = 0.974 and 0.926, respectively), whereas the hydroxylation influenced to a lesser extent the inhibitory potencies for serine/threonine protein kinase. The hydroxy residues at position 3' and 5' did not affect the activities of cAMP-dependent protein kinase, and protein kinase C, and the hydroxylation at position 5' is detrimental for the inhibition of MLC-kinase, and casein kinase I and II. Thus, flavonoids may be useful tools to elucidate the active site of tyrosine and serine/threonine protein kinases.
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PMID:Differential effects of flavonoids as inhibitors of tyrosine protein kinases and serine/threonine protein kinases. 316 98

The mechanisms of signaling pathways shared by interleukin (IL)-11, IL-6, leukemia inhibitory factor (LIF), and oncostatin M (ONC) remain elusive. We report here that treatment of 3T3-L1 cells with IL-11, IL-6, LIF, and ONC induces overlapping but distinct patterns of tyrosine phosphorylation and activates indistinguishable primary response genes. We further demonstrate for the first time that IL-11, IL-6, LIF, and ONC can trigger the activation of mitogen-activated protein kinases and the 85-92-kDa ribosomal S6 protein kinase (pp90rsk). In addition, our data also show that preincubation of cells with a tyrosine kinase inhibitor herbimycin A, but not with a serine/threonine kinase inhibitor H7, blocks activation of mitogen-activated protein kinases and pp90rsk. Interestingly, H7, but not herbimycin A, inhibits pp90rsk activity in the in vitro kinase assays. These results suggest that pp90rsk is one of the potential candidates for the H7-sensitive protein kinase(s), which is critical for the activation of primary response genes by these cytokines.
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PMID:Mitogen-activated protein kinases and ribosomal S6 protein kinases are involved in signaling pathways shared by interleukin-11, interleukin-6, leukemia inhibitory factor, and oncostatin M in mouse 3T3-L1 cells. 750 17

To identify novel proteins capable of associating with the Raf-1 serine/threonine kinase, we investigated whether Raf-1 could interact with the Src homology 2 (SH2) domains of various signal-transducing molecules. In this report, we demonstrate that Raf-1 associated with the SH2 domain of Fyn (a member of the Src tyrosine kinase family) but not with the SH2 domains of phospholipase C-gamma 1, the p85 alpha subunit of phosphatidylinositol 3-kinase, and SH2-containing protein tyrosine phosphatase 2. Unlike most SH2 domain interactions that require tyrosine-phosphorylated residues, the Raf-1/Fyn SH2 domain association was dependent on the serine phosphorylation of Raf-1. Our results also demonstrate that Raf-1 interacted with the SH2 domain of Src and that this interaction was destabilized by mutation of Arg175 found within the conserved SH2 domain FLVRES sequence. In addition, we show that inclusion of additional Src sequences containing the SH3 domain increased the association of Raf-1 with the Src SH2 domain. Finally, using the baculovirus/Sf9 cell system, we show that coexpression of Raf-1 with full-length Fyn/Src resulted in the coimmunoprecipitation of Raf-1 with Fyn/Src, the tyrosine phosphorylation of Raf-1, and the stimulation of Raf-1 kinase activity. These results suggest that Raf-1 may form a functional complex with Fyn/Src mediated in part by SH2 domains and the serine phosphorylation of Raf-1.
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PMID:Raf-1 interacts with Fyn and Src in a non-phosphotyrosine-dependent manner. 751 1

We have studied the signal transduction pathways of fibroblast growth factor receptor-4 (FGFR-4) and FGFR-1, which showed virtually identical acidic fibroblast growth factor binding profiles as well as tyrosine autophosphorylation upon activation in transfected L6 rat myoblasts and NIH3T3 mouse fibroblasts. A prominently tyrosyl-phosphorylated doublet of polypeptides of 85 kDa coprecipitated with activated FGFR-4 from both cell lines studied, but these polypeptides were not detected upon immunoprecipitation of activated FGFR-1. Furthermore, FGFR-4 induced only a weak tyrosyl phosphorylation of phospholipase C-gamma and no detectable tyrosyl phosphorylation of the SHC adaptor proteins in contrast to FGFR-1. No phosphorylation of Ras GTPase-activating protein, p64 Syp/PTP1D tyrosine phosphatase, or association of the GRB2 adaptor protein SH2 domain with these receptors was detected. Unlike FGFR-1, FGFR-4 induced only a barely detectable phosphorylation of the cellular serine/threonine kinase Raf-1 and a weaker tyrosyl phosphorylation of mitogen-activated protein kinases than FGFR-1. Despite these differences, stimulation of both receptors resulted in increased DNA synthesis.
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PMID:Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. 751 29

Lipopolysaccharide (LPS) or a combination of interferon (IFN)-gamma and interleukin (IL)-1 beta can induce a calcium-independent nitric oxide synthase (iNOS) in astrocyte cultures (Simmons and Murphy: J Neurochem 59:897, 1992; Eur J Neurosci 5:825, 1993; Galea et al: Proc Natl Acad Sci USA 89:10945, 1992). This induction can be measured by assaying cyclic GMP levels in the cultures, which correlates with, but is more sensitive than, measurement of nitrite accumulation. To study potential second-messenger systems involved in the induction of iNOS, phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, and various protein kinase inhibitors were employed. PMA induced a time-, dose-, and L-arginine-dependent increase in cyclic GMP, which could be inhibited by dexamethasone or actinomycin D. This induction could be dramatically increased by concurrent treatment with IFN-gamma. The presence of iNOS mRNA could be demonstrated by hybridization with a specific cDNA probe. H7 (a non-specific serine/threonine kinase inhibitor) but not H89 (a more specific PKA inhibitor) prevented induction by all agents. However, downregulation of PKC or pretreatment with the PKC inhibitor calphostin C did not prevent the induction by LPS or cytokines, suggesting that PKC is not necessary for iNOS induction by these mediators. Additionally, genistein (a nonspecific tyrosine kinase inhibitor) could prevent induction by all agents, but the more specific inhibitor, tyrphostin, attenuated only NOS induction by LPS. These results suggest that activation of PKC can lead to, but is not necessary for, the induction of NOS in astrocytes and that there is a potential role for tyrosine kinases in NOS induction by LPS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Roles for protein kinases in the induction of nitric oxide synthase in astrocytes. 752 77


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