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)

Screening of mouse cDNA expression libraries with antibodies to phosphotyrosine resulted in repeated isolation of cDNAs that encode a novel mammalian protein kinase of 774 amino acids, termed Nek1. Nek1 contains an N-terminal protein kinase domain which is most similar (42% identity) to the catalytic domain of NIMA, a protein kinase which controls initiation of mitosis in Aspergillus nidulans. In addition, both Nek1 and NIMA have a long, basic C-terminal extension, and are therefore similar in overall structure. Despite its identification with anti-phosphotyrosine antibodies, Nek1 contains sequence motifs characteristic of protein serine/threonine kinases. The Nek1 kinase domain, when expressed in bacteria, phosphorylated exogenous substrates primarily on serine/threonine, but also on tyrosine, indicating that Nek1 is a dual specificity kinase with the capacity to phosphorylate all three hydroxyamino acids. Like NIMA, Nek1 preferentially phosphorylated beta-casein in vitro. In situ RNA analysis of nek1 expression in mouse gonads revealed a high level of expression in both male and female germ cells, with a distribution consistent with a role in meiosis. These results suggest that Nek1 is a mammalian relative of the fungal NIMA cell cycle regulator.
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PMID:A mammalian dual specificity protein kinase, Nek1, is related to the NIMA cell cycle regulator and highly expressed in meiotic germ cells. 138 74

Entry into mitosis in Schizosaccharomyces pombe is negatively regulated by the wee1+ gene, which encodes a protein kinase with serine-, theonine-, and tyrosine-phosphorylating activities. The wee1+ kinase negatively regulates mitosis by phosphorylating p34cdc2 on tyrosine 15, thereby inactivating the p34cdc2-cyclin B complex. The human homolog of the wee1+ gene (WEE1Hu) was overproduced in bacteria and assayed in an in vitro system. Unlike its fission yeast homolog, the product of the WEE1Hu gene encoded a tyrosine-specific protein kinase. The human WEE1 kinase phosphorylated the p34cdc2-cyclin B complex on tyrosine 15 but not on threonine 14 in vitro and inactivated the p34cdc2-cyclin B kinase. This inhibition was reversed by the human Cdc25C protein, which catalyzed the dephosphorylation of p34cdc2. These results indicate that the product of the WEE1Hu gene directly regulates the p34cdc2-cyclin B complex in human cells and that a kinase other than that encoded by WEE1Hu phosphorylates p34cdc2 on threonine 14.
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PMID:Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. 138 26

Crosslinking of sIgM on the B cell line WEHI 231 with anti-sIgM antibody induces protein tyrosine phosphorylation, implicating protein tyrosine kinases (PTKs) in sIg-mediated signal transduction. We have analyzed this cell line for members of the src family of PTKs and have evaluated whether these PTKs might be involved in the process of sIgM-mediated signaling. Our results show that Blk, Lyn, Lck, and Hck are detectable in WEHI 231 cells. Addition of antibodies to sIgM were found to variably stimulate the activities of Blk, Lyn, Lck, and Hck as measured by immune-complex protein kinase assays. Autophosphorylation of these src PTKs, as assessed by reaction with anti-phosphotyrosine antibodies, increased over the time course of sIgM-mediated activation. Co-immunoprecipitation studies to investigate the potential physical interaction of src PTKs with the sIgM receptor complex revealed that, under digitonin and Brij 96 lysis conditions Lyn, Lck, Hck, but not Blk associated with sIgM.
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PMID:Cross-linking of surface immunoglobulin activates src-related tyrosine kinases in WEHI 231 cells. 138 74

In this work we report that CD5, a T cell accessory activation antigen and receptor for the B cell surface protein CD72, is associated with the T cell antigen receptor (TcR)/CD3 complex in human T lymphocytes. In vitro phosphorylation of either CD3 or CD5 immunoprecipitates prepared from CD3-stimulated Jurkat and peripheral blood T cells in the presence of the detergent polyoxyethelene 10 oleyl ether (Brij96) showed, unexpectedly, an identical pattern of five phosphopolypeptides of 70, 59, 56, 21 and 18 kDa, respectively. Peptide mapping of the five bands demonstrated that the same protein kinase substrates co-precipitated with both CD3 and CD5 and that the majority of the protein phosphorylation occurred on tyrosine residues. These data suggested that the TcR/CD3 complex and and the CD5 antigen might be associated in T cells. Evidence to support this hypothesis was obtained from analysis of immunoprecipitates prepared from surface-iodinated T cells. Bands characteristic of the TcR and CD3 antigens were identified in CD5 immunoprecipitates and conversely, CD5 was identified in CD3 immunoprecipitates. Conformation that CD3 and CD5 co-precipitated in the presence of Brij96 was obtained by Western blotting. Quantitative immunodepletion demonstrated that between 10%-20% of cell surface CD5 was associated with the TcR/CD3 complex in Brij96 detergent lysates of human T cells and, furthermore, that this association was independent of T cell activation. The association of these two receptors provides a possible physical basis for the accessory role of the CD5 antigen in T cell activation.
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PMID:Evidence for an association between the T cell receptor/CD3 antigen complex and the CD5 antigen in human T lymphocytes. 138 58

A phosphoinositide kinase that can phosphorylate phosphatidylinositol (PtdIns) is present in 4G10 monoclonal antibody (mAb) phosphotyrosine immunoprecipitates isolated from T cells activated via the T cell antigen receptor (TCR).CD3 complex. This PtdIns kinase is not the PtdIns 3-kinase that associates with activated protein tyrosine kinases in fibroblasts, since Western blotting and immunoprecipitation experiments with antibodies specific for the p85 alpha subunit of the PtdIns 3-kinase indicate that this polypeptide is not immunoprecipitated by the 4G10 mAb from TCR.CD3-activated Jurkat cells. Moreover, immunoprecipitated PtdIns 3-kinase isolated from T cells with p85 antibodies is inhibited when PtdIns is presented in Nonidet P-40, whereas the PtdIns kinase activity present in 4G10 mAb phosphotyrosine immunoprecipitates is enhanced in the presence of Nonidet P-40. In vitro kinase assays of PtdIns 3-kinase immunoprecipitated with p85 antibodies from T cells indicate that it associates with a serine kinase that can phosphorylate a p85 polypeptide. However, no protein tyrosine kinase activity capable of tyrosine phosphorylating p85 in vitro associates with p85 alpha immunoprecipitates in quiescent or TCR.CD3-activated T cells. These data suggest that the TCR.CD3 complex does not regulate PtdIns 3-kinase activity by a mechanism that involves protein tyrosine kinases.
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PMID:Regulation of phosphoinositide kinases in T cells. Evidence that phosphatidylinositol 3-kinase is not a substrate for T cell antigen receptor-regulated tyrosine kinases. 138 26

A dominant negative mutant of Ras, M17 Ras, was used to study the role of Ras in receptor coupling of Raf-1 and B-Raf protein serine/threonine kinases (PSKs). We found that mutant Ras blocks serum- and 12-O-tetradecanoyl phorbol 13-acetate-induced activation of Raf-1 kinase in NIH3T3 cells and Raf-1 as well as B-Raf PSK stimulation by nerve growth factor (NGF) in PC12 pheochromocytoma cells. Mitogen stimulation of Raf kinase was measured by determination of Raf hyperphosphorylation and activity towards exogenous substrates and both of these events were inhibited in cells expressing M17 Ras. In contrast, tyrosine phosphorylation of a direct substrate of activated tyrosine kinase receptors, phospholipase C-gamma 1 (PLC-gamma 1), was unaffected. These data indicate that tyrosine phosphorylation of PLC-gamma 1 is not sufficient for growth induction in NIH3T3 cells and that Ras mediates signal transfer from activated membrane receptors to Raf kinases in the cytosol. As activated Raf induced differentiation in PC12 cells expressing M17 Ras we conclude that Raf kinase activation may be sufficient to account for this aspect of NGF function.
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PMID:Ras controls coupling of growth factor receptors and protein kinase C in the membrane to Raf-1 and B-Raf protein serine kinases in the cytosol. 138 20

Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated kinases (ERKs), are thought to act at an integration point for multiple biochemical signals because they are activated by a wide variety of extracellular signals, rapidly phosphorylated on threonine and tyrosine, and highly conserved. A critical protein kinase lies upstream of MAP kinase and stimulates the enzymatic activity of MAP kinase. The structure of this protein kinase, denoted MEK1, for MAP kinase or ERK kinase, was elucidated from a complementary DNA sequence and shown to be a protein of 393 amino acids (43,500 daltons) that is related most closely in size and sequence to the product encoded by the Schizosaccharomyces pombe byr1 gene. The MEK gene was highly expressed in murine brain, and the product expressed in bacteria phosphorylated the ERK gene product.
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PMID:The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. 141 46

The product of the c-raf-1 proto-oncogene is a cytoplasmic serine/threonine protein kinase that appears to be activated in signal transduction from a variety of cell-surface receptors. The mechanism of c-Raf activation upon stimulation of cell-surface receptors is not clear, but there seem to exist multiple pathways of activation which involve tyrosine and/or serine phosphorylation of the c-Raf protein in vivo. The activated state of Raf is reflected in an increased apparent molecular weight of the Raf protein in sodium dodecyl sulfate-polyacrylamide gels owing to hyperphosphorylation. The tumor promoter 12-O-tetradecanoyl phorbol 13-acetate (TPA) is one of the agents able to induce this hyperphosphorylation of Raf in vivo, suggesting that protein kinase C (PKC) may be involved in the activation of c-Raf in particular situations. Using recombinant baculoviruses expressing PKC and Raf polypeptides, we show here that conventional PKC types (alpha, beta, gamma) but not novel types (delta, zeta, eta) or the unrelated Mos kinase are able to activate c-Raf in a TPA-dependent manner upon coexpression in insect cells. Direct phosphorylation of the Raf protein with PKC in vitro also enhanced the kinase activity of c-Raf, suggesting that c-Raf acts immediately downstream of PKC in a protein kinase cascade which is triggered by TPA and may lead to transcriptional activation of TPA-inducible genes and tumor promotion.
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PMID:Activation of the c-Raf protein kinase by protein kinase C phosphorylation. 143 48

During the course of characterizing polymerase chain reaction products corresponding to protein kinases of a higher plant, Arabidopsis thaliana, we found a DNA fragment that potentially codes for a polypeptide with mosaic sequences of two classes of protein kinases, a tyrosine-specific and a serine/threonine-specific one. Overlapping complementary DNA (cDNA) clones coinciding with this fragment were isolated from an A. thaliana cDNA library. From their sequence analyses a protein kinase was predicted composed of 410 amino acid residues (APK1, Arabidopsis protein kinase 1), in which the kinase domain was flanked by short non-kinase domains. Upon expression of APK1 in Escherichia coli cells, several bacterial proteins became reactive with anti-phosphotyrosine antibody but not with the same antibody preincubated with phosphotyrosine, convincing us that APK1 phosphorylated tyrosine residues. APK1 purified from an over-producing E. coli strain showed serine/threonine kinase activity, and no tyrosine kinase activity, towards APK1 itself, casein, enolase, and myosin light chains. APK1 was thus concluded to be a novel type of protein kinase, which could phosphorylate tyrosine, serine, and threonine residues, though tyrosine phosphorylation seemed to occur only on limited substrates. Since the structure of the APK1 N-terminal portion was indicative of N-myristoylation, APK1 might associate with membranes and thereby contribute to signal transduction. The A. thaliana genome contained two APK1 genes close to each other (APK1a and APK1b).
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PMID:Novel protein kinase of Arabidopsis thaliana (APK1) that phosphorylates tyrosine, serine and threonine. 145 Mar 80

A fungal metabolite, radicicol, with a macrocyclic ring induced the reversal of transformed phenotypes of v-src-transformed fibroblasts (Rous sarcoma virus-transformed 3Y1 rat fibroblast) at a quite low concentration of 0.1 microgram/ml. Actin stress fibers reappeared in the transformed cells after treatment with radicicol. Radicicol reduced the intracellular level of autophosphorylation of p60v-src as well as the level of other tyrosine-phosphorylated proteins in a dose-dependent manner. In vitro kinase assay revealed that radicicol effectively inhibited not only autophosphorylation but also transphosphorylation activities of purified p60v-src with a concentration producing 50% inhibition of 0.1 microgram/ml. However, radicicol showed no inhibitory effect on protein kinase C or protein kinase A. These results suggest that radicicol is a novel and specific protein-tyrosine kinase inhibitor and that the decreased level of tyrosine kinase activity of p60v-src causes reversion of transformed phenotypes of Rous sarcoma virus-transformed 3Y1 rat fibroblast. Furthermore, differentiation of Friend leukemia cells, which is one of the known characteristic phenomena associated with the inhibition of tyrosine kinase, was also induced in the concentration range of 0.05-0.5 microgram/ml, suggesting that the agent is useful for the analysis of differentiation as well as the kinase-mediated signal transduction.
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PMID:Potent and specific inhibition of p60v-src protein kinase both in vivo and in vitro by radicicol. 145 81


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