| Constitutive association of c-N-Ras with c-Raf-1 and protein kinase C epsilon in latent signaling modules. | |
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MedLine Citation:
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PMID: 11358964 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Phorbol ester stimulation of the MAPK cascade is believed to be mediated through the protein kinase C (PKC)-dependent activation of Raf-1. Although several studies suggest that phorbol ester stimulation of MAPK is insensitive to dominant-negative Ras, a requirement for Ras in Raf-1 activation by PKC has been suggested recently. We now demonstrate that in normal, quiescent mouse fibroblasts, endogenous c-N-Ras is constitutively associated with both c-Raf-1 and PKC epsilon in a biochemically silent, but latent, signaling module. Chemical inhibition of novel PKCs blocks phorbol 12-myristate 13-acetate (PMA)-mediated activation of MAPKs. Down-regulation of PKC epsilon protein levels by antisense oligodeoxyribonucleotides blocks MAPK activation in response to PMA stimulation, demonstrating that PKC epsilon activity is required for MAPK activation by PMA. c-Raf-1 activity in immunoprecipitated c-N-Ras.c-Raf-1.PKC epsilon complexes is stimulated by PMA and is inhibited by GF109203X, thereby linking c-Raf-1 activation in this complex to PKC activation. These observations suggest that in quiescent cells Ras is organized into ordered, inactive signaling modules. Furthermore, the regulation of the MAPK cascade by both Ras and PKC is intimately linked, converging at the plasma membrane through their association with c-Raf-1. |
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Authors:
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M Hamilton; J Liao; M K Cathcart; A Wolfman |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2001-05-17 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 276 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2001 Aug |
Date Detail:
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Created Date: 2001-07-30 Completed Date: 2001-09-13 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 29079-90 Citation Subset: IM |
Affiliation:
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Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. hamilton_mark@lilly.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cell Line, Transformed Cell Membrane / metabolism Culture Media, Serum-Free Enzyme Activation Epidermal Growth Factor / pharmacology Fibroblasts Genes, ras Guanosine Triphosphate / metabolism Isoenzymes / genetics, isolation & purification, metabolism* Kinetics Mice Oligodeoxyribonucleotides, Antisense / pharmacology Protein Kinase C / genetics, isolation & purification, metabolism* Protein Kinase C-epsilon Proto-Oncogene Proteins c-raf / isolation & purification, metabolism* Proto-Oncogene Proteins p21(ras) / isolation & purification, metabolism* Recombinant Fusion Proteins / metabolism Signal Transduction / drug effects, physiology* Tetradecanoylphorbol Acetate / pharmacology* Transfection |
| Grant Support | |
ID/Acronym/Agency:
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GM62644/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Culture Media, Serum-Free; 0/Isoenzymes; 0/Oligodeoxyribonucleotides, Antisense; 0/Recombinant Fusion Proteins; 16561-29-8/Tetradecanoylphorbol Acetate; 62229-50-9/Epidermal Growth Factor; 86-01-1/Guanosine Triphosphate; EC 2.7.1.-/Prkce protein, mouse; EC 2.7.11.1/Proto-Oncogene Proteins c-raf; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.13/Protein Kinase C-epsilon; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras) |
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