Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.25 (triphosphatase)
 1,529 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological activity of Ras proteins is thought to be controlled by the guanine nucleotide exchange factor and the guanosine triphosphatase activating protein (GAP). Treatment of rat pheochromocytoma PC-12 cells with nerve growth factor (NGF) increased the amount of active Ras guanosine triphosphate complex and stimulated the activities of both the guanine nucleotide exchange factor and GAP. In PC-12 cells that overexpressed the tyrosine kinase encoded by the trk proto-oncogene (a component of the high-affinity NGF receptor), the NGF-induced activation of the regulatory proteins was potentiated. These results suggest that the NGF receptor system enhances the activities of both the guanine nucleotide exchange factor and GAP and that the activation of Ras might be controlled by the balance in activity between these two regulatory proteins.
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PMID:Nerve growth factor stimulation of the Ras-guanine nucleotide exchange factor and GAP activities. 160 23

Ras-GAP (GTPase activating protein) is a regulatory protein that stimulates the intrinsic guanosine triphosphatase (GTPase) activity of the proto-oncogene product p21ras. A domain of the neurofibromatosis gene product (NF1) that has sequence similarity to the catalytic domain of Ras-GAP and to yeast IRA gene products also has a specific stimulatory activity toward p21ras GTPase. Arachidonic acid and phosphatidic acid inactivate GAP, but no agents have been identified that stimulate GAP and thereby switch p21ras off. With the use of recombinant Ha-c-Ras and Ras-GAP, NF1, and GAP catalytic domains, it was found that prostaglandins PGF2 alpha and PGA2 stimulated Ras-GAP and that prostacyclin PGI2 inhibited Ras-GAP. The stimulatory effect of PGF2 alpha was saturable and structure-specific and competed with the inhibitory effect of arachidonic acid. Arachidonic acid also inhibited the catalytic activity of NF1, but prostaglandins were not stimulatory. These results suggest a mechanism for the allosteric control of Ras function through the modulation of arachidonate metabolism.
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PMID:Regulation of Ras-GAP and the neurofibromatosis-1 gene product by eicosanoids. 190 23

The ras proto-oncogene products appear to relay intracellular signals via the Ras guanosine triphosphatase (GTPase) activator protein, GAP. In dog epithelial cells expressing human platelet-derived growth factor (PDGF) receptors, binding of PDGF caused approximately one-tenth of the total GAP molecules to complex with the receptor. Studies with mutant PDGF receptors showed that maximum association required both receptor kinase activity and phosphorylatable tyrosine residues at both the identified sites of receptor autophosphorylation.
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PMID:Binding of GAP to activated PDGF receptors. 215 84

1. The expression of c-raf protooncogene in early stages of chemically induced rat liver tumorigenesis was studied in weanling female and adult male Sprague-Dawley rats. After initiation with diethylnitrosamine, promotion by polychlorinated biphenyls (PCBs) or phenobarbital (PB) was studied in the female. Male rats were promoted with PCBs only. 2. The incidence of enzyme-altered foci was evaluated histochemically by demonstrating a deficiency in adenosine-5'-triphosphatase and the emergence of gamma-glutamyl-transpeptidase. C-raf expression was measured in liver tissue containing preneoplastic foci, and in small (< 3 mm in diameter) and large (> 3 mm in diameter) neoplastic nodules up to 36 weeks. 3. Foci numbers amounted to 60-70 per cm2 liver section with both histochemical markers and both promoters in female rats. In male rats foci numbers were about 20-40 per cm2 liver section with both markers and with PCBs as promoting agents. Foci area developed more rapidly in female rats. 4. Small and large nodules were found in females during the entire observation period with both promoting agents, PCBs being more effective than PB. C-raf expression in nodules was increased up to 10-fold in PCB-treated animals compared with untreated controls. No dependence on the size of the nodules was seen. In male rats nodule incidence was very low and c-raf induction was marginal. 5. In conclusion, c-raf proto-oncogene expression correlated with the incidence of foci and nodules, female rats being more sensitive than males.
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PMID:C-raf expression in early rat liver tumorigenesis after promotion with polychlorinated biphenyls or phenobarbital. 752 61

Yes belongs to the Src family of protein-tyrosine kinases. In order to understand molecular aspects of its signaling, we decided to isolate proteins that bind to the modulatory region of the Yes molecule. By generating anti-idiotypic antibodies against the aminoterminal domain of the Yes protein, we have identified, characterized and cloned a cDNA for a novel protein that binds to the Src homology domain 3 (SH3) of the Yes proto-oncogene product. The protein is of 65 kiloDalton (kDa) molecular mass, it is phosphorylated in vivo on serine and is particularly rich in proline. We named it YAP65 for Yes-Associated Protein of 65 kDa. Within the YAP65 sequence, we identified a motif, PVKQPPPLAP, similar to that found in proteins that bind to the SH3 domain of the Abl kinase. Competition assays with synthetic peptides showed the involvement of the predicted proline-rich sequence in binding between YAP65 and the Yes kinase. The YAP65 protein was also shown to bind to other signaling molecules that contain SH3 domains including Nck, Crk and Src. At lower stoichiometry, YAP65 was also shown to bind to the SH3 domains of Abl and guanosine triphosphatase activating protein (GAP). Further characterization of YAP65 should illuminate Yes signaling pathways and could also identify a novel link between protein-tyrosine and serine kinases.
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PMID:Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. 803 99

Unlike the alpha subunits of heterotrimeric guanosine triphosphate (GTP)-binding proteins, Ras-related GTP-binding proteins have hitherto been considered not to bind or become activated by tetrafluoroaluminate (AIF4-). However, the product of the proto-oncogene ras in its guanosine diphosphate (GDP)-bound form interacted with AIF4 - in the presence of stoichiometric amounts of either of the guanosine triphosphatase (GTPase)-activating proteins (GAPs) p120GAP and neurofibromin. Neither oncogenic Ras nor a GAP mutant without catalytic activity produced such a complex. Together with the finding that the Ras-binding domain of the protein kinase c-Raf, whose binding site on Ras overlaps that of the GAPs, did not induce formation of such a complex, this result suggests that GAP and neurofibromin stabilize the transition state of the GTPase reaction of Ras.
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PMID:Formation of a transition-state analog of the Ras GTPase reaction by Ras-GDP, tetrafluoroaluminate, and GTPase-activating proteins. 865 79

A review of the meeting "The Ras Superfamily of Small GTP-Binding Proteins," FASEB Summer Research Conference, Snowmass, Colorado, 15 through 20 July 2000 The molecular cloning of the human proto-oncogene encoding Ras was reported nearly 20 years ago. Since then, Ras has become the prototypical member of a superfamily of small guanosine triphosphatase proteins. Despite the maturity of this field of research, the discovery of new functions and interactions between the superfamily members continues unabated. Symons and Takai have written a meeting report on the latest findings on the Ras superfamily.
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PMID:Ras GTPases: singing in tune. 1175 38

Hepatocellular carcinoma often reactivates the genes that are transiently expressed in fetal or neonatal livers. However, the mechanism of their activation has not been elucidated. To explore how oncogenic signaling pathways could be involved in the process, we examined the expression of fetal/neonatal genes in liver tumors induced by the introduction of myristoylated v-akt murine thymoma viral oncogene (AKT), HRas proto-oncogene, guanosine triphosphatase (HRASV12), and MYC proto-oncogene, bHLH transcription factor (Myc), in various combinations, into mouse hepatocytes in vivo. Distinct sets of fetal/neonatal genes were activated in HRAS- and HRAS/Myc-induced tumors: aldo-keto reductase family 1, member C18 (Akr1c18), glypican 3 (Gpc3), carboxypeptidase E (Cpe), adenosine triphosphate-binding cassette, subfamily D, member 2 (Abcd2), and trefoil factor 3 (Tff3) in the former; insulin-like growth factor 2 messenger RNA binding protein 3 (Igf2bp3), alpha fetoprotein (Afp), Igf2, and H19, imprinted maternally expressed transcript (H19) in the latter. Interestingly, HRAS/Myc-induced tumors comprised small cells with a high nuclear/cytoplasmic ratio and messenger RNA (mRNA) expression of delta-like noncanonical Notch ligand 1 (Dlk1), Nanog homeobox (Nanog), and sex determining region Y-box 2 (Sox2). Both HRAS- and HRAS/Myc-induced tumors showed decreased DNA methylation levels of Line1 and Igf2 differentially methylated region 1 and increased nuclear accumulation of 5-hydroxymethylcytosine, suggesting a state of global DNA hypomethylation. HRAS/Myc-induced tumors were characterized by an increase in the mRNA expression of enzymes involved in DNA methylation (DNA methyltransferase [Dnmt1, Dnmt3]) and demethylation (ten-eleven-translocation methylcytosine dioxygenase 1 [Tet1]), sharing similarities with the fetal liver. Although mouse hepatocytes could be transformed by the introduction of HRAS/Myc in vitro, they did not express fetal/neonatal genes and sustained global DNA methylation, suggesting that the epigenetic alterations were influenced by the in vivo microenvironment. Immunohistochemical analyses demonstrated that human hepatocellular carcinoma cases with nuclear MYC expression were more frequently positive for AFP, IGF2, and DLK1 compared with MYC-negative tumors. Conclusion: The HRAS signaling pathway and its interactions with the Myc pathway appear to reactivate fetal/neonatal gene expression in hepatocytic tumors partly through epigenetic alterations, which are dependent on the tumor microenvironment.
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PMID:Emergence of the Dedifferentiated Phenotype in Hepatocyte-Derived Tumors in Mice: Roles of Oncogene-Induced Epigenetic Alterations. 3106 57