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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2004-3-23
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pubmed:databankReference |
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pubmed:abstractText |
Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Braf protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/MAP2K1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Map2k1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphotransferases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins B-raf,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-raf
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0092-8674
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pubmed:author |
pubmed-author:BarfordDavidD,
pubmed-author:Cancer Genome Project,
pubmed-author:GarnettMathew JMJ,
pubmed-author:GoodValerie MVM,
pubmed-author:JonesC MichaelCM,
pubmed-author:LeeSharleneS,
pubmed-author:MaraisRichardR,
pubmed-author:MarshallChristopher JCJ,
pubmed-author:Niculescu-DuvazDanD,
pubmed-author:RoeS MarkSM,
pubmed-author:SpringerCaroline JCJ,
pubmed-author:WanPaul T CPT
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pubmed:issnType |
Print
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pubmed:day |
19
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pubmed:volume |
116
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
855-67
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15035987-Allosteric Regulation,
pubmed-meshheading:15035987-Animals,
pubmed-meshheading:15035987-Catalytic Domain,
pubmed-meshheading:15035987-Cell Transformation, Neoplastic,
pubmed-meshheading:15035987-Enzyme Inhibitors,
pubmed-meshheading:15035987-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:15035987-MAP Kinase Kinase 1,
pubmed-meshheading:15035987-MAP Kinase Signaling System,
pubmed-meshheading:15035987-Mice,
pubmed-meshheading:15035987-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:15035987-Mitogen-Activated Protein Kinases,
pubmed-meshheading:15035987-Models, Molecular,
pubmed-meshheading:15035987-Molecular Conformation,
pubmed-meshheading:15035987-Mutation,
pubmed-meshheading:15035987-NIH 3T3 Cells,
pubmed-meshheading:15035987-Neoplasms,
pubmed-meshheading:15035987-Oncogenes,
pubmed-meshheading:15035987-Oocytes,
pubmed-meshheading:15035987-Phosphorylation,
pubmed-meshheading:15035987-Phosphotransferases,
pubmed-meshheading:15035987-Proto-Oncogene Proteins B-raf,
pubmed-meshheading:15035987-Proto-Oncogene Proteins c-raf,
pubmed-meshheading:15035987-Up-Regulation,
pubmed-meshheading:15035987-Xenopus
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pubmed:year |
2004
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pubmed:articleTitle |
Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
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pubmed:affiliation |
Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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