| Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase. | |
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MedLine Citation:
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PMID: 7692235 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The serine/threonine kinase activity of the Raf-1 proto-oncogene product is stimulated by the activation of many tyrosine kinases, including growth factor receptors and pp60v-src. Recent studies of growth factor signal transduction pathways demonstrate that Raf-1 functions downstream of activated tyrosine kinases and p21ras and upstream of mitogen-activated protein kinase. However, coexpression of both activated tyrosine kinases and p21ras is required for maximal activation of Raf-1 in the baculovirus-Sf9 expression system. In this study, we investigated the role of tyrosine kinases and tyrosine phosphorylation in the regulation of Raf-1 activity. Using the baculovirus-Sf9 expression system, we identified Tyr-340 and Tyr-341 as the major tyrosine phosphorylation sites of Raf-1 when coexpressed with activated tyrosine kinases. Introduction of a negatively charged residue that may mimic the effect of phosphorylation at these sites activated the catalytic activity of Raf-1 and generated proteins that could transform BALB/3T3 cells and induce the meiotic maturation of Xenopus oocytes. In contrast, substitution of noncharged residues that were unable to be phosphorylated produced a protein that could not be enzymatically activated by tyrosine kinases and that could block the meiotic maturation of oocytes induced by components of the receptor tyrosine kinase pathway. These findings demonstrate that maturation of the tyrosine phosphorylation sites can dramatically alter the function of Raf-1. In addition, this is the first report that a transforming Raf-1 protein can be generated by a single amino acid substitution. |
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Authors:
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J R Fabian; I O Daar; D K Morrison |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Molecular and cellular biology Volume: 13 ISSN: 0270-7306 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 1993 Nov |
Date Detail:
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Created Date: 1993-11-18 Completed Date: 1993-11-18 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 7170-9 Citation Subset: IM |
Affiliation:
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Molecular Mechanisms of Carcinogenesis Laboratory, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702-1201. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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3T3 Cells Amino Acid Sequence Animals Cell Line Female Gene Expression Mice Molecular Sequence Data Moths Oocytes / metabolism Phosphoprotein Phosphatases / metabolism Phosphorylation Phosphotyrosine Protein-Serine-Threonine Kinases / metabolism* Protein-Tyrosine Kinases / metabolism Proto-Oncogene Proteins / genetics*, metabolism* Proto-Oncogene Proteins c-raf Transfection Tyrosine* / analogs & derivatives, analysis Xenopus laevis |
| Grant Support | |
ID/Acronym/Agency:
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N01-CO-74101/CO/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Proto-Oncogene Proteins; 21820-51-9/Phosphotyrosine; 55520-40-6/Tyrosine; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-raf; EC 3.1.3.16/Phosphoprotein Phosphatases |
| Comments/Corrections | |
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