Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of polyoma virus to transform cells results primarily from the action of one of the virus-coded early proteins, called middle-T antigen. Middle-T has an associated tyrosine-specific protein kinase activity that can be measured in vitro and results in the phosphorylation of middle-T itself. Almost all mutants so far tested that lack the ability to transform cells, also lack associated kinase activity. Attempts to map within middle-T the tyrosine residue(s) that are phosphorylated in vitro suggest that a likely site of phosphorylation is tyrosine 315 (refs 8-10 and unpublished results). The amino acid sequence preceding Tyr 315 includes a tract of six contiguous glutamic acid residues and bears some homology with that preceding the tyrosine phosphorylated in vivo in pp60v-src, the transforming protein of Rous sarcoma virus, and with a region in the polypeptide hormone, gastrin, preceding a tyrosine that is sulphated. Furthermore, although surprisingly large tracts of middle-T may be removed without affecting its transforming activity, mutants that lack the sequences corresponding to amino acids 311-318 inclusive are transformation defective. Because the likely site of phosphorylation, the homology with pp60v-src and gastrin and the sequence apparently required for transformation all overlap, it has generally been accepted that this region of middle-T may form part of an essential region, possibly an active site on the protein. Here we have used techniques of site-directed and site-specific mutagenesis to probe the sequence requirements in more detail. Contrary to expectation, the results obtained strongly suggest that Tyr 315 and conservation of the surrounding amino acid sequence are not essential for transformation.
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PMID:Transforming activity of polyoma virus middle-T antigen probed by site-directed mutagenesis. 630 61

The nucleotide sequence of the region of Gardner-Rasheed feline sarcoma virus (GR-FeSV) encoding its primary translation product, p70gag-fgr, has been determined. From the nucleotide sequence, the amino acid sequence of this transforming protein was deduced. Computer analysis indicates that a portion of P70gag-fgr has extensive amino acid sequence homology with actin, a eukaryotic cytoskeletal protein. A second region of P70gag-fgr is closely related to the tyrosine-specific kinase gene family. Thus, the v-fgr oncogene appears to have arisen as a result of recombinational events involving two distinct cellular genes, one coding for a structural protein and the other for a protein kinase.
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PMID:Gene product of v-fgr onc: hybrid protein containing a portion of actin and a tyrosine-specific protein kinase. 631 14

We have recently proposed that the transforming protein of polyoma virus, middle-T antigen, forms a complex with pp60c-src. Here we provide additional evidence for the existence of the complex using both monoclonal antibodies specific for middle-T and antibodies raised against synthetic peptides corresponding to sequences from both middle-T and pp60c-src. The complex was retained during partial purification of middle-T and was stable to incubation under various conditions. A survey of a number of mutants of middle-T antigen showed that there was a complete correlation between the ability of middle-T to accept phosphate in the in vitro kinase reaction and the presence of a middle-T: pp60c-src complex. This result is in accord with our hypothesis that middle-T itself is not a protein kinase but rather that pp60c-src phosphorylates middle-T. All mutant forms of middle-T antigen capable of transformation had associated pp60c-src. The middle-T of two non-transforming mutants (hr-t mutants) did not have associated pp60c-src, whereas other non-transforming middle-T species did associate with pp60c-src. We propose that the complex plays an essential role in transformation by polyoma virus, but that the existence of the complex per se may not be sufficient.
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PMID:The complex of polyoma virus middle-T antigen and pp60c-src. 632 77

Transformation by Rous sarcoma virus results in a dramatic increase in the rate at which the transformed cells transport glucose across the cell membrane. The increased transport rate is a consequence of an increased number of transporters in the transformed cells. Utilizing antibody raised against the purified human erythrocyte glucose transporter, we have identified the glucose transporter as a membrane glycoprotein with a monomer Mr of approximately 41,000. The increased rate of glucose transport is dependent on the activity of pp60src, the transforming protein of Rous sarcoma virus. This protein has been shown to be a protein kinase that phosphorylates on tyrosine residues. We have examined the tyrosine phosphorylation of a major cellular protein of Mr 36,000 in cells infected with a panel of partially transforming mutants of Rous sarcoma virus. One of these mutants (CU2) increases the rate of glucose transport only slightly and does not render the infected cells fully anchorage independent or tumorigenic (although other transformation parameters are fully induced). Cells infected with this mutant display a 36,000-dalton protein that is phosphorylated to a considerably lesser extent than cells infected with wild-type virus. Analyses of this sort may help to identify the cellular targets of pp60src whose phosphorylation is necessary for the increased glucose transport rate.
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PMID:Molecular events leading to enhanced glucose transport in Rous sarcoma virus-transformed cells. 632 50

The transforming protein of avian sarcoma virus UR2, p68v-ros, has an associated tyrosine-specific protein kinase activity similar to that of p60v-src and several other oncogene products. However, this activity has not been linked unequivocally to transformation, and the physiological action of these proteins remains in doubt. We now have found that immunoprecipitated p68v-ros also is associated with phosphatidylinositol (PtdIns) kinase (ATP:PtdIns 4-phosphotransferase, EC 2.7.1.67) activity. PtdIns 4,5-bisphosphate [PtdIns(4,5)P2] specifically inhibits both this activity and the autophosphorylation of p68v-ros. Moreover, cells transformed by UR2 showed significant increases in 32P-labeling of PtdIns 4-phosphate (PtdIns4P) and PtdIns(4,5)P2 and in the formation of their catabolites, inositol 1,4-bisphosphate and inositol 1,4,5-trisphosphate, as compared to uninfected cells. These results suggest that a physiologically relevant function of oncogene kinases might be the phosphorylation of PtdIns and that increased turnover of PtdIns4P and PtdIns(4,5)P2 might play a role in transformation by increasing the formation of diacylglycerol, a catabolite of polyphosphoinositides that activates kinase C. This protein copurifies with the phorbol ester receptor, and its activation is likely to be intimately linked with mitogenesis. This hypothesis suggests a mechanism whereby certain oncogene proteins might cause the unrestricted growth typical of transformed cells and could explain why tumor promoters mimic many of the effects of transformation.
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PMID:Transforming protein of avian sarcoma virus UR2 is associated with phosphatidylinositol kinase activity: possible role in tumorigenesis. 632 40

The 130 kd transforming protein of Fujinami sarcoma virus (FSV P130gag -fps) possesses a tyrosine-specific protein kinase activity and is itself phosphorylated at several tyrosine and serine residues in FSV-transformed cells. We have used oligonucleotide-directed mutagenesis of the FSV genome to change the TAT codon for tyrosine (1073), the major site of P130gag -fps phosphorylation, to a TTT codon for phenylalanine that cannot be phosphorylated. This mutant FSV induces the transformation of rat-2 cells but with a long latent period as compared with wild-type FSV. The P130gag -fps protein encoded by the mutant retains the ability to phosphorylate tyrosine, but is five times less active as a kinase in vitro than wild-type FSV P130gag -fps. These data indicate that tyrosine phosphorylation stimulates the biochemical and biological activities of FSV P130gag -fps, and they set a precedent for the ability of this amino acid modification to modulate protein function.
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PMID:Mutagenesis of Fujinami sarcoma virus: evidence that tyrosine phosphorylation of P130gag-fps modulates its biological activity. 632 76

The protooncogene c-fps/fes is a single vertebrate locus homologous to both the fps transforming gene of Fujinami avian sarcoma virus and the fes transforming gene of two feline sarcoma virus isolates. The human c-fps/fes locus has been previously cloned and characterized. We report that a recombinant gene in which 3' human c-fps/fes sequences replace over 80% of the feline sarcoma virus fes sequences transforms NIH 3T3 mouse fibroblasts and encodes a protein kinase. Cells transformed by this recombinant possess increased phosphotyrosine levels. These observations demonstrate that a large carboxyl portion of a human c-fps/fes protein product can functionally complement a retroviral transforming protein.
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PMID:Transforming potential of a human protooncogene (c-fps/fes) locus. 632 90

Fujinami sarcoma virus (FSV) and PRCII avian sarcoma virus both encode gag-fps transforming proteins associated with tyrosine-specific protein kinase activity; however, PRCII has a lower oncogenic potential than does FSV. In this study, the genomes of PRCII and FSV have been compared. By hybridization of PRCII [32P]RNA to FSV DNA on Southern blots, a large internal deletion in the 5' half of the fps gene in PRCII has been mapped. To determine the exact size and location of the deletion in PRCII, dideoxy sequencing of PRCII RNA with FSV DNA fragments as primers was used. The FSV sequence corresponding to the deletion in PRCII was flanked by 6-base direct repeats ( AGCTGG ) at 1614-1619 and 2634-2639 nucleotides. One copy of the direct repeat was retained in the PRCII genome. The length of the deleted region was 1020 nucleotides. The deletion in fps did not alter the kinase domain or ATP-binding site of the P105 transforming protein of PRCII. It was shown that the specific kinase activity of P105 was as high as that of FSV P130 . The sequence deleted from PRCII was found to encode part of a large hydrophilic domain. In the accompanying paper [J. Woolford and K. Beemon (1984) Virology 135, 168-180], evidence that the PRCII and FSV proteins have different subcellular locations and solubility properties, possibly due to the loss of this domain, is presented. These alterations in the structure and location of the PRCII protein may prevent it from phosphorylating certain substrates involved in oncogenic transformation.
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PMID:The avian sarcoma virus PRCII lacks 1020 nucleotides of the fps transforming gene. 632 46

Enolase, lactate dehydrogenase, and phosphoglycerate mutase have previously been found to contain phosphotyrosine in fibroblasts transformed by Rous sarcoma virus, which encodes a tyrosine-specific protein kinase. However, these phosphorylations are not stoichiometric, and their significance for any aspect of the transformed phenotype is unknown. We show here that enolase and lactate dehydrogenase are each phosphorylated chiefly at a single tyrosine in Rous sarcoma virus-transformed cells. The purified enzymes can also be phosphorylated at the same tyrosine in vitro when incubated with an immunoprecipitated retroviral transforming protein having associated tyrosine protein kinase activity. The phosphorylated tyrosine in lactate dehydrogenase is amino acid 238. The phosphorylated tyrosine in enolase lies in a sequence homologous to that surrounding histidine 43 in yeast enolase. Although the phosphorylated sequence in lactate dehydrogenase shows some homology to those sequences surrounding phosphotyrosines found in retroviral transforming proteins, the phosphorylated sequence in enolase is quite different.
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PMID:Phosphorylation sites in enolase and lactate dehydrogenase utilized by tyrosine protein kinases in vivo and in vitro. 633 85

A glycoprotein-enriched fraction derived from 3T3-L1 adipocyte membranes by Triton X-100 extraction and chromatography on wheat germ agglutinin-agarose contains an insulin-activable protein kinase that catalyzes the phosphorylation of tyrosine residues in proteins (Petruzzelli, L. M., Ganguly, S., Smith, C.J., Cobb, M. H., Rubin, C.S., and Rosen, O. M. (1982) Proc. Natl. Acad. Sci. U. S. A. 79, 6792-6796). The best peptide substrates for the enzyme are angiotensin II, and a synthetic peptide related to the amino acid sequence surrounding the site of tyrosine phosphorylation in the transforming protein kinase of Rous sarcoma virus. Kinetic analysis of the phosphorylation reaction with angiotensin II showed that insulin decreased the Km from 5.0 to 2.6 mM, and increased the Vmax from 0.6 to 2.2 pmol/min/10 fmol of insulin binding capacity. For the src-related peptide, the addition of insulin decreased the Km from 1.6 to 1.2 mM and increased the Vmax from 0.17 to 2.2 pmol/min/10 fmol of insulin binding capacity. Angiotensin III inhibitor, proctolin, beta-lipotropin (61-65) and Tyr-Arg were poorer substrates for the protein kinase. Protein substrates for the insulin-stimulated protein kinase include anti-src IgG, tubulin, casein, and histone H2b. The data suggest that the substrate specificity of the insulin-activable protein kinase is similar to that reported for the src and epidermal growth factor receptor protein kinases.
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PMID:Phosphorylation of exogenous substrates by the insulin receptor-associated protein kinase. 640 86


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