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)

Novel p21 phosphorylation was found in cells expressing high levels of this product of c-H- and c-K-ras genes. Phorbol 12,13-dibutyrate, a protein kinase C (PKC) activator, and permeable c-AMP derivatives, which activate protein kinase A (PKA), stimulated phosphorylation of K-ras(4B) p21 in 416B cells 3 to 5 fold. By tryptic peptide mapping, it was found that both PKC and PKA phosphorylated in vitro the K-ras p21 at the same site as was found in p21 from cells labeled with [32P]orthophosphate in vivo. A common site of H-ras p21 was also phosphorylated by both PKC and PKA, although phosphopeptides of H-ras p21 were distinct from those of K-ras p21. The construction of a mutant by site-directed mutagenesis allowed the identification of serine-177 as the phosphorylation site of H-ras p21. This novel phosphorylation site lies in the hypervariable region, which links the globular catalytic domain of p21 to the membrane-anchoring site at the C-terminus, a location suggesting that this phosphorylation plays a role in modulating transmembrane signaling.
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PMID:Novel phosphorylation of c-ras p21 by protein kinases. 284 44

We have purified to near homogeneity a Mr 22,000 GTP-binding protein from human platelet membranes and identified it as the smg-21 gene product (smg p21), having the same putative effector domain as the ras gene products, which we have purified to near homogeneity from bovine brain membranes and characterized. This purified human platelet smg p21 was phosphorylated by cyclic AMP-dependent protein kinase. About one mol of phosphate was maximally incorporated into one mol of the protein. Only serine residue was phosphorylated. Both the guanosine 5'-(3-O-thio)-triphosphate (GTP gamma S)-bound and GDP-bound forms were phosphorylated with the same reaction velocity. The phosphorylation of smg p21 affected neither its GTP gamma S-binding nor GTPase activity. Human platelet smg p21 was not phosphorylated by protein kinase C. A Mr 24,000 GTP-binding protein partially purified from human platelet membranes was not phosphorylated by cyclic AMP-dependent protein kinase or protein kinase C.
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PMID:Phosphorylation by cyclic AMP-dependent protein kinase of a human platelet Mr 22,000 GTP-binding protein (smg p21) having the same putative effector domain as the ras gene products. 284 42

Factors that control cellular proliferation might do so by regulating quantitative expression of viral or cellular oncogenes. Since the growth regulatory effect of cAMP is well-known, the effect of cAMP on ras gene expression was examined on Ha-MuSV-transformed 13-3B-4 cells (NIH-3T3) grown in chemically defined serum-free medium. Treatment of cells with two classes of cAMP analogs which are selective for the two different cAMP-binding sites of type II protein kinase, in combination, synergistically inhibited both p21 ras protein synthesis and phenotypic transformation. The inhibition was also demonstrated with these analogs singly but at higher concentrations. The decrease in p21 synthesis was inversely correlated with an increase in the RII cAMP receptor protein, the regulatory subunit of type II protein kinase. These results suggest a role for cAMP and its receptor protein in the regulation of v-rasH oncogene expression.
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PMID:Two classes of cAMP analogs synergistically inhibit p21 ras protein synthesis and phenotypic transformation of NIH/3T3 cells transfected with Ha-MuSV DNA. 299 3

We have found that, when isolated rat liver mitochondria are incubated with [gamma-32P]ATP, there is phosphorylation of 36- and 17-kDa proteins. These proteins together with their protein kinase(s) are released as a complex by incubation of the isolated rat liver mitochondria at 20 degrees C for 30 min with 10 mM glucose 6-phosphate, 0.5 mM inositol phosphate, or 0.01 mM inositol triphosphate. Phosphorylation of the 36- and 17-kDa proteins in this soluble protein fraction is modulated by p21 proteins encoded by ras oncogenes and synthesized in Escherichia coli via recombinant DNA methods. A normal p21 ras protein stimulates phosphorylation of the 36-kDa protein and inhibits phosphorylation of the 17-kDa protein, whereas two transforming p21 ras proteins inhibit phosphorylation of both the 36- and 17-kDa proteins. Although GDP and 5'-guanylyl imidodiphosphate also influence the phosphorylation of these proteins, we present evidence that the effects of p21 ras protein are not simply due to their bound GDP. This novel system may be useful for further studies on the biochemical functions of the p21 ras proteins.
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PMID:p21 ras proteins and guanine nucleotides modulate the phosphorylation of 36- and 17-kilodalton mitochondria-associated proteins. 309 13

Multiple kinases interact at the multicomponent murine T cell antigen receptor. Antigen induces serine phosphorylation of the 21-kDa gamma glycoprotein and tyrosine phosphorylation of p21, a distinct 21-kDa chain. We demonstrate that tyrosine phosphorylation is due to kinase activation, and that all phosphorylated p21 is associated with the antigen receptor. We also show that antigen leads to polyphosphoinositide metabolism and subsequent protein kinase C activation. The two phosphorylation events can be dissociated by protein kinase C depletion, which eliminates phorbol 12-myristate 13-acetate-induced serine but not tyrosine phosphorylation. Activation of a third kinase, cyclic AMP-dependent protein kinase, inhibits both serine and tyrosine events, yet this inhibition can be modulated by addition of the protein kinase C activator, phorbol 12-myristate 13-acetate. Receptor-mediated signal transduction may be understood as the interaction of multiple stimulatory and inhibitory kinase activities.
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PMID:Multiple kinases and signal transduction. Phosphorylation of the T cell antigen receptor complex. 349 29

The effects of protein kinase C inhibitor H-7 (1-(5-isoquinolinylsulfonyl)-2-methylpiperazine) on tumor-promoting phorbol ester induced inhibition of vincristine uptake in P388 murine leukemic cells were investigated with the objective of assessing the possible role of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C) in vincristine uptake. 12-O-Tetradecanoylphorbol-13-acetate (TPA) is a potent inhibitor at concentrations above 1 nM. Other phorbol esters also inhibited vincristine uptake in approximate proportion to their activity in competing for [20-3H]phorbol 12,13-dibutrate binding. TPA enhanced the Ca2+-activated, phospholipid-dependent phosphorylation of histone III-S by a soluble protein fraction of cells. Phosphorylation of various cell lysate proteins (p18, p21, p29, p34 and p45) were also stimulated by TPA. These TPA-induced stimulations were also inhibited dose-dependently by H-7. It is tentatively concluded that the phosphorylation of cell lysate protein substrates by protein kinase C may be an important mechanism linked to the regulation of vincristine uptake in leukemic cell.
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PMID:An inhibitor of protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine(H-7) inhibits TPA-induced reduction of vincristine uptake from P388 murine leukemic cell. 376 16

The structural proteins of mouse mammary tumor virus (MMTV) were analyzed by two-dimensional electrophoresis on isoelectric focusing and sodium dodecyl sulfate gels. Many of the viral proteins displayed heterogeneity in charge due to variable contents of carbohydrates (in particular, sialic acid) and phosphate residues. Neuraminidase treatment of the virions influenced the isoelectric pattern of the envelope glycoproteins. The glycoproteins of an MMTV variant which was attenuated by replication in feline kidney cells had different isoelectric points. This suggested that the acquisition of an altered carbohydrate configuration had changed the host range of the virus. The major MMTV structural core protein, p27, consisted of two species, which had identical iodinated tryptic peptide compositions but differed in phosphate contents. Another MMTV phosphoprotein, p21, was separated into four different phosphorylated species. Phosphorylation of p21 could be performed in vitro by the MMTV virion-associated protein kinase. This enzyme also has a high affinity for MMTV p30 as a substrate. Possible functions of this enzyme are discussed.
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PMID:Analysis of secondary modifications of mouse mammary tumor virus proteins by two-dimensional gel electrophoresis. 625 75

The WAF1 gene, located on chromosome 6p, encodes a M(r) 21,000 protein (p21) that can arrest cell growth by associating with and inhibiting cyclin-dependent kinase complexes that are necessary for cells to exit Gr. Transcriptional activation of WAF1 can be accomplished by increasing levels of p53 protein induced by various cellular stresses, including DNA damage. Metastatic melanomas are paradoxical in that most overexpress wild-type p53 protein, yet cell growth is not inhibited. Thus, it is possible that lack of growth suppression in melanomas is due, in part, to mutations in the WAF1 gene. Therefore, we examined the entire coding region of the WAF1 gene in 24 metastatic melanoma cell lines and three normal melanocyte lines by single-strand conformation polymorphism (SSCP) analysis and direct DNA sequencing. We similarly examined the DNA from lymphoblastoid cell lines, derived from nine individuals belonging to seven melanoma-prone families, in which haplotypes of markers on 6p cosegregate with melanoma for germline mutations in the WAF1 gene. Results indicate that (i) mutation of the WAF1 gene is an infrequent event in individuals with sporadic melanoma or predisposed to familial melanoma and (ii) the uncontrolled growth of melanoma cells is not due to mutation of the WAF1 gene. However, expression studies found a wide variation in the level of p21 protein in melanoma cells, suggesting that aberrant regulation of p21 may play a role in melanoma development. Moreover, there was no predictable relationship between p21 expression and p53 expression, indicating that other, p53-independent, pathways may be important for the regulation of p21 in melanoma cells.
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PMID:Mutations and defective expression of the WAF1 p21 tumour-suppressor gene in malignant melanomas. 749 59

We have recently found that ralGDS family members (RGL and ralGDS) are putative effector proteins of ras p21. rap1 p21 is a small GTP-binding protein which has the same amino acid sequence as the effector loop of ras p21. We examined the effect of rap1 p21 on the interaction of ras p21 with RGL. The GTP-bound form of rap1 p21 interacted with RGL as well as did ras p21. rap1 p21 inhibited the interaction of ras p21 with RGL. RGL was phosphorylated by cyclic AMP-dependent protein kinase (protein kinase A). Phosphorylation of RGL did not affect its binding to ras p21 and rap1 p21 under the conditions that phosphorylation of Raf-1 reduced its affinity for ras p21. These results demonstrate that rap1 p21 but not protein kinase A regulates the interaction of ras p21 with RGL and suggest that rap1 p21 and protein kinase A may cooperate to distinguish the signal or ras p21 to RGL from that to Raf-1.
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PMID:rap1 p21 regulates the interaction of ras p21 with RGL, a new effector protein of ras p21. 749 75

We have selected yeast mutants that exhibit a constitutively active pheromone-response pathway in the absence of the beta subunit of the trimeric G protein. Genetic analysis of one such mutant revealed that it contained recessive mutations in two distinct genes, both of which contributed to the constitutive phenotype. One mutation identifies the RGA1 locus (Rho GTPase activating protein), which encodes a protein with homology to GAP domains and to LIM domains. Deletion of RGA1 is sufficient to activate the pathway in strains lacking the G beta subunit. Moreover, in wild-type strains, deletion of RGA1 increases signaling in the pheromone pathway, whereas over-expression of RGA1 dampens signaling, demonstrating that Rga1p functions as a negative regulator of the pheromone response pathway. The second mutation present in the original mutant proved to be an allele of a known gene, PBS2, which encodes a putative protein kinase that functions in the high osmolarity stress pathway. The pbs2 mutation enhanced the rga1 mutant phenotype, but by itself did not activate the pheromone pathway. Genetic and two-hybrid analyses indicate that an important target of Rga1p is Cdc42p, a p21 GTPase required for polarity establishment and bud emergence. This finding coupled with recent experiments with mammalian and yeast cells indicating that Cdc42p can interact with and activate Ste20p, a protein kinase that operates in the pheromone pathway, leads us to suggest that Rga1p controls the activity of Cdc42p, which in turn controls the magnitude of signaling in the pheromone pathway via Ste20p.
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PMID:Mutation of RGA1, which encodes a putative GTPase-activating protein for the polarity-establishment protein Cdc42p, activates the pheromone-response pathway in the yeast Saccharomyces cerevisiae. 749 91


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