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)

Oncornaviruses, which contain a virion-associated protein kinase, were found to possess phosphoproteins as virion structural components. One major phosphoprotein common to strains of laboratory and wild mouse oncornaviruses and a strain of feline leukemia virus was shown to be a polypeptide of about 12, 000 mol wt. In addition to this, the Kirsten strain of murine sarcoma virus contained a second major phosphoprotein of about 10, 000 mol wt, and mouse erythroblastosis virus contained a second major phosphoprotein that was either identical to or comigrated with the virion glycoprotein of about 74, 000 mol wt. The major phosphoprotein of RD-114 virus was found to be of about 16, 000 mol wt. The major phosphoamino acid of the 12, 000-mol wt polypeptide of the mouse erythroblastosis virus was identified as phosphoserine, and that of the 16, 000-mol wt polypeptide of the RD-114 virus was identified as phosphothreonine.
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PMID:Phosphoproteins: structural components of oncornaviruses. 16 71

Sera from certain rabbits bearing Schmidt-Ruppin strain Rous sarcoma virus (RSV)-induced tumors precipitated p60(src) from chicken cells transformed by the homologous virus as well as by other strains [Prague strain RSV, Bryan high-titer strain RSV, and Bratislava 77 strain of avain sarcoma virus (ASV)], the molecular weights (M(r)s) ranging from 60,000 to 64,000. The p60(src) immunoprecipitated from cells transformed by each of these strains incorporated [gamma-(32)P]ATP into the M(r) 53,000 subunit of IgG, though with differing activities. No such protein kinase activity (ATP:protein phosphotransferase, EC 2.7.1.37) was observed when the following immunoprecipitates were used: from uninfected cells, from untransformed cells infected by Rous-associated virus, or from cells transformed by acute leukosis viruses, avian erythroblastosis virus, or myelocytoma virus 29. The kinase reaction had a pH optimum at pH 5.9 and an apparent K(m) for ATP of 4.9 +/- 2 muM, and was dependent on Mg(2+) (K(b) = 46 +/- 12 mM), for which Ca(2+) was no substitute. The kinase was cyclic AMP independent. In order to test whether the protein kinase reaction is directly catalyzed by p60(src), we compared the in vitro temperature sensitivities of the kinase activities from cells infected by transformation-temperature-sensitive mutant and parental wild-type virus. The first-order rate constant for the inactivation of the kinase from extracts of cells infected by the mutant virus was 2-fold greater than that from cells infected by wild-type virus. This result implicates the protein kinase as an enzymatic activity of the src gene product, the p60(src). Concomitant with the loss of the kinase activity by heat inactivation, p60(src) loses 60-70% of its phosphate content. The kinetics of dephosphorylation exactly parallel those for the inactivation of the kinase activity, suggesting that the p60(src) kinase is itself dependent on phosphorylation for its activity.
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PMID:Src Gene product from different strains of avian sarcoma virus: Kinetics and possible mechanism of heat inactivation of protein kinase activity from cells infected by transformation-defective, temperature-sensitive mutant and wild-type virus. 21 25

The v-erbA oncogene of avian erythroblastosis virus (AEV) encodes a ligand-independent mutated version of the chicken c-erbA alpha-encoded thyroid hormone receptor. The v-erbA gene product, a 75-kD gag/v-erbA fusion protein, is phosphorylated on Ser-16/17 of its v-erbA-encoded domain, and phosphorylation at this site is increased in vivo after activation of either the PKA or PKC signal transduction pathways. To test the hypothesis that phosphorylation of Ser-16/17 regulates gag/v-erbA protein function, mutant proteins in which Ser-16/17 had been changed to alanine or threonine residues were analyzed for their ability to inhibit erythroid differentiation of ts v-erbB or ts v-sea-transformed erythroblasts at nonpermissive temperature. Conversion of Ser-16/17 into alanine, although not affecting nuclear localization or DNA binding of the gag/erbA protein, prevented phosphorylation of the v-erbA-encoded domain of the protein both in unstimulated cells or after stimulation by PKA and PKC activators. The nonphosphorylatable AA-gag/v-erbA protein proved unable to inhibit temperature-induced differentiation of ts v-erbB and ts v-sea-transformed erythroblasts and to block expression of the erythrocyte-specific genes band 3 and carbonic anhydrase II. Back mutation of these alanine residues to serine resulted in the recovery of both normal phosphorylation levels and wild-type biological activity. In contrast, substitution of Ser-16/17 for threonine, which preserved phosphorylation in unstimulated cells but not PKA- and PKC-enhanced phosphorylation, resulted in a partially active gag/v-erbA protein. These results, together with the fact that the protein kinase inhibitor H7 resulted in both a dose-dependent inhibition of gag/v-erbA protein phosphorylation and the induction of terminal differentiation of AEV-transformed erythroblasts show that phosphorylation of gag/v-erbA protein is required for full biological activity. These results support the hypothesis that phosphorylation of the gag/v-erbA protein is important for transcriptional repression of at least some of its target genes in erythroid cells.
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PMID:Phosphorylation of the v-erbA protein is required for its function as an oncogene. 197 40

The c-erbA alpha progenitor of the v-erbA oncogene of avian erythroblastosis virus (AEV) encodes a nuclear receptor for the thyroid hormone triiodothyronine (T3) which acts as a ligand-dependent transcription factor. As previously reported (Goldberg et al., EMBO J., 7, 2425-2433), the 46 kd chicken c-erbA alpha-encoded T3 receptor (ck-ErbA alpha) is phosphorylated at two major sites. Only one of these sites (Ser28/Ser29) is retained in the v-erbA-encoded P75gag-v-erbA protein. We report here the identification of the second phosphorylation site of ck-ErbA alpha as a single serine residue localized at position 12. We propose that casein kinase II, a protein kinase distributed in the cytosolic and nuclear compartments of a number of different tissues, is responsible for serine 12 phosphorylation on the following grounds. First, serine 12 is part of a sequence containing multiple acidic amino-acids, a feature common to all sites phosphorylated by casein kinase II in physiological substrates. Second, ck-ErbA alpha was found to be phosphorylated by purified casein kinase II in vitro at the same site, as defined by two-dimensional mapping experiments, as that observed in vivo. Third, conversion of serine 12 into an unphosphorylatable alanine residue by site directed mutagenesis abolishes the phosphorylation of ck-ErbA alpha by casein kinase II in vitro. Phosphorylation of serine 12 is likely to play a role in the modulation of ErbA alpha function since both serine 12 and the casein kinase II phosphorylation sequence motif are phylogenetically conserved in all known members of the c-erbA alpha gene family encoding T3 binding proteins. The codon specifying serine 12 in ck-ErbA alpha being precisely the point where recombination between gag and ck-c-erbA alpha occurred to generate v-erbA, our results furthermore suggest that deletion of serine 12 could contribute to the oncogenic activation of v-erbA.
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PMID:The c-erbA alpha-encoded thyroid hormone receptor is phosphorylated in its amino terminal domain by casein kinase II. 255 74

The epidermal growth factor (EGF) receptor is a plasma membrane glycoprotein. It contains four distinct segments: an N-terminal EGF binding domain which is exposed at the cell surface; a short transmembrane segment; a cytoplasmic domain with protein-tyrosine kinase activity; and a C-terminal regulatory segment. Binding of EGF to the external domain of the receptor activates the protein-tyrosine kinase activity of the receptor, and this elevated kinase activity is presumed to be involved in the activation of cell growth. The v-erbB transforming gene of avian erythroblastosis virus is derived, by retroviral transduction, from the gene (c-erbB) which encodes the avian EGF receptor. The transforming capacity of v-erbB appears to result from truncation of the receptor. In erythroid cells, truncation of the N-terminal ligand binding domain is sufficient for transformation, whereas in fibroblasts removal of an additional C-terminal segment is required for transformation. The EGF receptor is subject to complex regulatory controls, including ligand activation, downregulation by internalization, autophosphorylation and autoregulation and transmodulation involving phosphorylation by kinase C. This review is centered around the hypothesis that the transforming capacity of the truncated v-erbB gene product results from a loss in sensitivity to regulators and the consequent activation of protein kinase activity.
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PMID:The erbB gene and the EGF receptor. 287 33

A library of recombinant bacteriophage was prepared from ts167 avian erythroblastosis virus-transformed erythroid precursor cells (HD6), and integrated proviruses from three distinct genomic loci were isolated. A subclone of one of these proviruses (pAEV1) was shown to confer temperature-sensitive release from transformation of erythroid precursor cells in vitro. The predicted amino acid sequence of the v-erbB polypeptide from the mutant had a single amino acid change when compared with the wild-type parental virus. When the wild-type amino acid was introduced into the temperature-sensitive avian erythroblastosis virus provirus in pAEV1, all erythroid clones produced in vitro were phenotypically wild type. The mutation is a change from a histidine to an aspartic acid in the temperature-sensitive v-erbB polypeptide. It is located in the center of the tyrosine-specific protein kinase domain and corresponds to amino acid position 826 of the human epidermal growth factor receptor sequence.
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PMID:A single amino acid substitution in v-erbB confers a thermolabile phenotype to ts167 avian erythroblastosis virus-transformed erythroid cells. 287 64

The c-erbA proto-oncogene encodes a nuclear receptor for thyroid hormone (T3), which is believed to stimulate transcription from specific target promoters upon binding to cis-acting DNA sequence elements. The v-erbA oncogene of avian erythroblastosis virus (AEV) encodes a ligand-independent version of this nuclear receptor. The v-erbA product inhibits terminal differentiation of avian erythroblasts, presumably by affecting the transcription of specific genes. We show here that the c-erbA-encoded nuclear receptor (p46c-erbA) is phosphorylated on serine residues on two distinct sites. One of these sites, defined by the limit tryptic phosphopeptide 28SSQCLVK, is retained on the v-erbA-encoded P75gag-v-erbA protein. This site is located in the amino-terminal domain of these molecules, 21 amino acids upstream of the DNA-binding region. Phosphorylation of this site in both p46c-erbA and P75gag-v-erbA is enhanced 10-fold following treatment of cells with activators of either protein kinase C or cAMP-dependent protein kinase. Since cAMP-dependent protein kinase phosphorylates both p46c-erbA and P75gag-v-erbA in vitro at the same site as that observed in vivo, at least part of the cAMP-dependent phosphorylation of erbA molecules in cells could result from direct phosphorylation by this enzyme. The possible role phosphorylation may play in the function of the erbA-encoded transcriptional factors is discussed.
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PMID:Activation of protein kinase C or cAMP-dependent protein kinase increases phosphorylation of the c-erbA-encoded thyroid hormone receptor and of the v-erbA-encoded protein. 290 25

The v-erbB gene product of avian erythroblastosis virus (AEV) has extensive homology with the receptor for epidermal growth factor (EGF). We report here that chicken embryo fibroblasts (CEF) transformed by AEV show enhanced tyrosine phosphorylation of a number of cellular polypeptides, including the 36 kd protein, which is phosphorylated in avian sarcoma virus-transformed fibroblasts, and the 42 kd protein, which is phosphorylated in mitogen-stimulated cells. CEF infected by AEV mutants with deletions in v-erbA showed enhanced tyrosine phosphorylation, whereas CEF infected by mutants with deletions in v-erbB did not. When membranes from AEV-transformed cells were incubated with gamma-32P-ATP, both the v-erbB gene product and the 36 kd cellular protein became phosphorylated at tyrosine. These results indicate that the v-erbB protein induces tyrosine phosphorylation in vivo and in vitro, and suggest that, like the EGF receptor, it possesses tyrosine-specific protein kinase activity.
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PMID:Protein phosphorylation at tyrosine is induced by the v-erbB gene product in vivo and in vitro. 298

The transforming protein erbB of avian erythroblastosis virus (AEV) has considerable sequence homology with the epidermal growth factor (EGF) and appears to represent a truncated form of this receptor. The sequence of the erbB gene is furthermore related to that of other viral transforming genes such as src, fps, yes or abl. The transforming proteins of these src-related oncogenes as well as receptors for EGF, platelet-derived growth factor (PDGF), and insulin are associated with tyrosine-specific protein kinases. It has been difficult to demonstrate this activity for the erbB protein. To analyze the erbB gene product, we prepared polyclonal antibodies against a bacterially expressed erbB DNA restriction fragment (BamHI/BamHI). The antiserum is shown to immunoprecipitate the erbB protein from AEV-transformed chicken fibroblasts and also recognizes the EGF receptor protein. Both proteins become phosphorylated in vitro on tyrosine residues upon the addition of [gamma-32P]ATP. The protein kinase activity is low compared to other oncogene-specific kinases. This is not due to kinase blocking by the serum, because erbB carboxyterminal synthetic peptide antibodies give rise to low levels of protein kinase activity as well indicating that this may be a characteristic property of erbB in vitro.
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PMID:Analysis of a tyrosine-specific protein kinase activity associated with the retroviral erbB oncogene product. 299 15

The v-erb B protein of avian erythroblastosis virus (AEV) possesses an associated protein kinase activity in vitro. Analysis of temperature-sensitive mutants, and nonconditional host range mutants of AEV demonstrated that there was no simple correlation between this autophosphorylation activity and the transformation ability of the various AEV mutants. These data suggest that although this kinase activity may be central to transformation by AEV it is in itself insufficient.
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PMID:Analysis of the autophosphorylation activity of transformation defective mutants of avian erythroblastosis virus. 300 40


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