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)

A 70-kDa protein is phosphorylated in cell-free preparations from rat or mouse fibroblasts by an endogenous protein kinase. This protein is immunologically related to a group of 68-kDa to 87-kDa proteins described in the literature as substrates for protein kinase C (PK-C). Although the phosphorylation of the 70-kDa protein by isolated plasma membranes takes place in the presence of EGTA, we conclude that the reaction is catalyzed by PK-C based on its inhibition by staurosporin. As shown previously, pure PK-C phosphorylates a synthetic random polymer of arginine and serine in the absence of Ca2+ and lipids, a reaction markedly stimulated by an endogenous unidentified activator of PK-C. When the 70-kDa protein from normal fibroblasts was exposed to the cytosol of chemically or ras-transformed fibroblasts, it disappeared as measured by phosphorylation by added PK-C. Cytosol of normal fibroblasts was much less effective (ca. 20%). Cathepsin L purified from rat kidney or from the medium of transformed cells had an effect similar to that of the cytosol of transformed cells. When the 70-kDa protein was phosphorylated by PK-C prior to exposure to cathepsin L or to the cytosol of transformed cells, there was a marked protection of the 70-kDa protein. We conclude that the 70-kDa protein is degraded by cathepsin L as ascertained by both immunological and biochemical assays and that it is protected by prior phosphorylation with PK-C. The possible role of this effect in signal transduction is discussed.
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PMID:Decreased susceptibility of a 70-kDa protein to cathepsin L after phosphorylation by protein kinase C. 249 61

We have separated multiple small Mr GTP-binding proteins (G proteins) from bovine brain membranes by several column chromatographies and purified to near homogeneity four of them, including a novel Mr 24,000 G protein (smg p25A), a novel Mr 22,000 G protein (smg p21), the rho protein (rho p20), and the c-Ki-ras protein (c-Ki-ras p21). Among these small Mr G proteins, only smg p21 is phosphorylated stoichiometrically by cAMP-dependent protein kinase (protein kinase A), and c-Ki-ras p21 is phosphorylated to a small extent by protein kinase A in a cell-free system. None of smg p25A, rho p20, and other partially purified small Mr G proteins is phosphorylated by protein kinase A. Neither smg p21 nor other small Mr G proteins are phosphorylated by protein kinase C. About 1 mol of phosphate is maximally incorporated into 1 mol of smg p21 by protein kinase A. Only serine residue(s) are phosphorylated. The guanosine 5'-3-O-(thio) triphosphate (GTP gamma S)-bound and GDP-bound forms of smg p21 are phosphorylated with the same reaction velocity. The phosphorylation of smg p21 affects neither its GTP gamma S-binding nor GTPase activity. smg p21 is found in human platelets, and this human platelet smg p21 is also phosphorylated by protein kinase A at the same site(s) as bovine brain smg p21 in a cell-free system. When intact human platelets are stimulated by prostaglandin E1 known to elevate the cAMP level, four proteins with apparent Mr values of 240,000, 50,000, 24,000, and 22,000 are phosphorylated. These four proteins are also phosphorylated by the action of dibutyryl cAMP but not by the action of thrombin, Ca2+ ionophore A23187, or 12-O-tetradecanoylphorbol-13-acetate. Among the four proteins, the Mr 22,000 protein is identified as smg p21. The site(s) of phosphorylation of smg p21 by protein kinase A in a cell-free system are identical to that phosphorylated in response to prostaglandin E1 in intact platelets. These results indicate that among many small Mr G proteins, smg p21 is selectively phosphorylated by protein kinase A and that this G protein is also phosphorylated by this protein kinase in response to prostaglandin E1 in intact human platelets.
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PMID:Phosphorylation of smg p21, a ras p21-like GTP-binding protein, by cyclic AMP-dependent protein kinase in a cell-free system and in response to prostaglandin E1 in intact human platelets. 250 24

A site-selective cAMP analog, 8-chloroadenosine 3',5'-cyclic monophosphate (8-Cl-cAMP), was demonstrated to be a potent inhibitor of both the monolayer and soft agar growth of normal rat kidney (NRK) fibroblasts that had been transformed with the v-Ki-ras oncogene or treated with transforming growth factor alpha (TGF alpha). The growth inhibition was dose dependent and reversible and was accompanied by reversion of the transformed phenotype, suppression of TGF alpha production, and a decrease in p21 ras protein levels. These effects of 8-Cl-cAMP were linked to the cAMP analog's selective modulation of the type I and type II cAMP-dependent protein kinase regulatory subunits, RI and RII, present in Ki-ras-transformed and TGF alpha-treated NRK cells.
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PMID:Site-selective 8-chloroadenosine 3',5'-cyclic monophosphate inhibits transformation and transforming growth factor alpha production in Ki-ras-transformed rat fibroblasts. 253 20

Alteration of oncogene and loss of chromosomal heterozygosity are infrequent in human gastric carcinoma compared with those in other gastrointestinal carcinomas. Amplification of c-erbB-2 gene is observed in well differentiated adenocarcinoma, while sam gene is found in poorly differentiated adenocarcinoma or scirrhous carcinoma. sam gene, which was isolated from a gastric cancer cell line KATO-III by a DNA renaturation method, encodes tyrosine-specific protein kinase domain. A good correlation evidently exists between the synchronous expression of TGF alpha and ras p21 and biological malignancy of gastric carcinoma. c-myc and c-fos proteins are found not only in tumor cells but also in stromal cells including macrophages and fibroblast around the tumors. The prognosis of patients with c-myc p 62-positive stromal cells is significantly better than that of patient with p 62-negative stromal cells. Coamplification of the hst-1 gene and int-2 is observed in 50% of primary tumors and all metastatic tumors of esophageal carcinoma. PCR (polymerase chain reaction) technique seems to be useful for the detection of oncogene point mutation in human gastric carcinoma.
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PMID:[Oncogenes in human gastric carcinoma]. 254 46

The yeast Saccharomyces cerevisiae contains two functionally redundant genes RAS1 and RAS2, which are homologous to the mammalian ras gene family and are required for vegetative growth. We isolated and characterized five temperature-sensitive alleles of RAS2. In a ras1 strain, these alleles cause growth arrest at the G1 stage of the cell cycle. Revertants capable of growth at the nonpermissive temperature define four recessive, extragenic complementation groups. Suppressors in one complementation group (designated yak1) are particularly intriguing because they appear to alleviate only the growth defect of the temperature-sensitive ras mutants and do not show any of the phenotypes, such as heat shock sensitivity or starvation sensitivity, associated with increased production of cAMP. The YAK1 gene has been cloned, and disruptions generated in vitro reveal that it is not essential for growth and that its loss confers growth to a strain deleted for tpk1, tpk2, and tpk3, the structural genes for the catalytic subunit of the cAMP-dependent protein kinase. These results place Yak1 downstream from, or on a parallel pathway to, the kinase step in the Ras/cAMP pathway. Finally, the coding region predicts a protein with significant homology to the family of protein kinases, suggesting that loss of cAMP-dependent protein kinase function can be suppressed by the loss of a second protein kinase.
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PMID:Loss of Ras activity in Saccharomyces cerevisiae is suppressed by disruptions of a new kinase gene, YAKI, whose product may act downstream of the cAMP-dependent protein kinase. 255 53

The E7 protein of human papillomavirus type 16 (HPV16) transforms cultured cells and cooperates with the ras or fos oncogenes in the transformation of primary cells. In this study we have investigated the phosphorylation of E7. When we immunoprecipitated E7 from CaSki cells with a rabbit polyclonal antiserum to a bacterial fusion protein (trpE-E7), we found that E7 was phosphorylated at serine residues contained in five characteristic thermolysin peptides. Immunoprecipitated E7, and fusion proteins harboring the E7 protein from various HPV types, could all be specifically phosphorylated in vitro by the ubiquitous, growth factor-activated casein kinase II (CKII). Comparative peptide mapping showed that the sites of in vivo and in vitro phosphorylation are the same. CKII was shown previously to specifically phosphorylate serine or threonine residues within a cluster of acidic amino acids. The E7 protein contains such a sequence between amino acids 30 and 37. When a synthetic peptide corresponding to this region of E7 was phosphorylated by CKII in vitro, its thermolysin digestion products were the same as those in the phosphorylated E7 protein. We conclude that E7 is phosphorylated in vivo only at serines within the predicted CKII site and that CKII, or a CKII-like enzyme, participates in the reaction. Both the E1A and SV40 large T proteins contain similar CKII consensus sites proximal to the regions required for their associations with the retinoblastoma gene product (p105Rb). Thus it is conceivable that CKII phosphorylation can modulate the interaction between the transforming proteins and the retinoblastoma gene product.
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PMID:The E7 protein of human papillomavirus type 16 is phosphorylated by casein kinase II. 256 89

A murine IgM monoclonal antibody, designated SV2-61, was generated against human c-erbB-2 gene-transfected NIH-3T3 (SV11) cells. SV2-61 defined a 185-kDa molecule present on the surface of SV11 cells, another line of c-erbB-2 gene-transfected NIH-3T3 (A4-15) cells, and MKN-7 human gastric cancer cell line carrying an amplified human c-erbB-2 gene. The SV2-61-defined antigen was found to show protein kinase activity in vitro. The SV2-61 was reactive with human c-erbB-2 gene-transfected NIH-3T3 cell lines but not with transfectants carrying c-erbB-2 gene mutants which lack a coding region for the extracellular domain. It was reactive with a portion of human epithelial cell lines but not with native NIH-3T3, TGF-alpha-coding gene-, activated c-raf gene- or Ha-ras gene-transfected NIH-3T3 cells, or non-epithelial human cells. These results indicate that the SV2-61 is an antibody which recognizes an extracellular domain of the c-erbB-2 gene product, 185-kDa protein.
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PMID:A murine monoclonal antibody that recognizes an extracellular domain of the human c-erbB-2 protooncogene product. 256 25

Mammalian tissues and cell lines express two major types of cAMP-dependent protein kinase, PKA-I and PKA-II, which can be distinguished at the molecular level by the presence of either type I or type II regulatory subunits in the holoenzyme. An expression vector for the mouse type II regulatory subunit (RII alpha) was transfected into ras-transformed NIH3T3 (R3T3) cells, which contain approximately equal amounts of both holoenzymes, PKA-I and PKA-II. In RII alpha-overexpressing R3T3 cells, PKA-II levels were increased, and the level of PKA-I declined. The decrease in PKA-I was dependent on the amount of RII alpha expressed, and at high levels of RII alpha expression, PKA-I was completely eliminated. In contrast, overexpression of the type I regulatory subunit (RI alpha) did not alter PKA isozyme levels. We propose that competition between RII alpha and RI alpha for a limited pool of catalytic subunit results in preferential assembly of PKA-II and that significant amounts of PKA-I are formed only if catalytic subunit is present in excess of the RII alpha subunit. The PKA-I isozyme, which is absent in untransformed 3T3 cells, is not essential for the transformed phenotype of R3T3 cells. RII alpha-overexpressing R3T3 cells that are devoid of PKA-I continued to exhibit a transformed phenotype including anchorage-independent growth. Overexpression of RII alpha provides a genetic approach that may prove useful in demonstrating specific functions for the two PKA isozymes in cAMP-dependent signal transduction pathways.
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PMID:Overexpression of the type II regulatory subunit of the cAMP-dependent protein kinase eliminates the type I holoenzyme in mouse cells. 258 16

The Xenopus laevis genome was probed by Southern Blot analysis for the presence of sequences homologous to mammalian or avian proto-oncogenes. Hybridization conditions were strictly defined with a known proto-oncogene to detect a positive signal with DNA sequences having at least 60 to 64% homology. In such conditions thirteen genes representing different oncogene families exhibited positive hybridizations with specific DNA restriction fragments. Members of the protein kinase oncogene family were detected including abl, erbB, fes, fms, ros, raf and mos. Ets, rel, and the steroid hormone related receptor erbA also gave positive signals with specific Xenopus DNA fragments. Proto-oncogenes raf and the ras family, N-ras, H-ras and c-ral, gave the strongest hybridizations and the signals remained positive in high stringency wash conditions. This study confirms the relative conservation of these genes during evolution and opens the possibility of studying their role in one of the best characterized systems of embryonic development.
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PMID:Detection of proto-oncogenes in the genome of the amphibian Xenopus laevis. 265 8

It is now established that ras oncogenes can induce metastatic characteristics in primary diploid fibroblasts, nonsenescing fibroblasts and nonmetastasizing tumors. The issue of whether ras is directly involved in maintaining the metastatic phenotype through the expression and action of its gene product has been examined by analyzing the relationship to ras expression and to the production of the p21 ras-GTP complex, which is thought to mediate ras-transforming activity. While these expression and mutation studies support the idea that p21 ras directly regulates metastasis formation, it is also evident that there are many examples of human and murine cancers which show no differences in ras expression in primary and metastatic tumor cells. This may be partially explained by the ability of protein kinase-encoding oncogenes to also induce metastatic potential. In addition, the ability of ras to induce metastasis may be dependent on the regulation of its activity by other genes. Furthermore, transformation does not occur as an isolated genetic event, but is rather the result of interaction of two or more oncogenes. We suggest that the nature of these gene interactions will ultimately determine whether a cell is a benign transformant or a malignant and metastatic cancer.
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PMID:Oncogenes and metastatic progression. 268 84


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