Show simple item record

dc.contributor.authorWan, PTC
dc.contributor.authorGarnett, MJ
dc.contributor.authorRoe, SM
dc.contributor.authorLee, S
dc.contributor.authorNiculescu-Duvaz, D
dc.contributor.authorGood, VM
dc.contributor.authorJones, CM
dc.contributor.authorMarshall, CJ
dc.contributor.authorSpringer, CJ
dc.contributor.authorBarford, D
dc.contributor.authorMarais, R
dc.contributor.authorCancer Genome Project
dc.date.accessioned2018-06-05T15:26:17Z
dc.date.issued2004-03
dc.identifier.citationCell, 2004, 116 (6), pp. 855 - 867
dc.identifier.issn0092-8674
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1727
dc.identifier.eissn1097-4172en_US
dc.identifier.doi10.1016/s0092-8674(04)00215-6en_US
dc.description.abstractOver 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.
dc.formatPrint
dc.format.extent855 - 867
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCancer Genome Project
dc.subjectOocytes
dc.subjectNIH 3T3 Cells
dc.subjectAnimals
dc.subjectXenopus
dc.subjectMice
dc.subjectNeoplasms
dc.subjectCell Transformation, Neoplastic
dc.subjectPhosphotransferases
dc.subjectProto-Oncogene Proteins B-raf
dc.subjectProto-Oncogene Proteins c-raf
dc.subjectMitogen-Activated Protein Kinase Kinases
dc.subjectMAP Kinase Kinase 1
dc.subjectMitogen-Activated Protein Kinases
dc.subjectEnzyme Inhibitors
dc.subjectMAP Kinase Signaling System
dc.subjectGene Expression Regulation, Enzymologic
dc.subjectUp-Regulation
dc.subjectAllosteric Regulation
dc.subjectCatalytic Domain
dc.subjectMolecular Conformation
dc.subjectPhosphorylation
dc.subjectMutation
dc.subjectOncogenes
dc.subjectModels, Molecular
dc.titleMechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
dc.typeJournal Article
dcterms.dateAccepted2004-02-02
rioxxterms.versionofrecord10.1016/s0092-8674(04)00215-6
rioxxterms.licenseref.startdate2004-03en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCell
pubs.issue6
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Gene & Oncogene Targeting
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Oncogene
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Signal Transduction
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Gene & Oncogene Targeting
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Oncogene
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Signal Transduction
pubs.publication-statusPublished
pubs.volume116en_US
pubs.embargo.termsNot known
pubs.oa-locationhttps://doi.org/10.1016/S0092-8674(04)00215-6
icr.researchteamGene & Oncogene Targetingen_US
icr.researchteamOncogeneen_US
icr.researchteamSignal Transductionen_US
dc.contributor.icrauthorMarshall, Christopheren
dc.contributor.icrauthorBarford, Daviden
dc.contributor.icrauthorMarais, Richard Malcolmen
dc.contributor.icrauthorSpringer, Carolineen
dc.contributor.icrauthorNiculescu-Duvaz, Danen


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record

http://creativecommons.org/licenses/by/4.0/
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/