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dc.contributor.authorRebocho, A
dc.contributor.authorMarais, Richard
dc.date.accessioned2013-08-30T13:00:49Z
dc.date.available2013-08-30T13:00:49Z
dc.date.issued2013-06-27
dc.identifier.citationARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers. 2013, 32 (26):3207-12 Oncogeneen_GB
dc.identifier.issn1476-5594
dc.identifier.pmid22926515
dc.identifier.doi10.1038/onc.2012.330
dc.identifier.urihttp://hdl.handle.net/10541/300411
dc.description.abstractThe RAF proteins are cytosolic protein kinases that regulate cell responses to extracellular signals. There are three RAF proteins in cells, ARAF, BRAF and CRAF, and recent studies have shown that the formation of complexes by these different isoforms has an important role in their activation, particularly in response to RAF inhibitors. Here, we investigated the role of ARAF in cancer cell signaling and examined the role of ARAF in mediating paradoxical activation of the MAPK pathway in cells treated with RAF inhibitors. We show that two mutations that occur in ARAF in cancer inactivate the kinase. We also show that ARAF is not functionally redundant with CRAF and cannot substitute for CRAF downstream of RAS. We further show that ARAF binds to and is activated by BRAF and that ARAF also forms complexes with CRAF. Critically, ARAF seems to stabilize BRAF:CRAF complexes in cells treated with RAF inhibitors and thereby regulate cell signaling in a subtle manner to ensure signaling efficiency.
dc.language.isoenen
dc.rightsArchived with thanks to Oncogeneen_GB
dc.titleARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers.en
dc.typeArticleen
dc.contributor.departmentThe Institute of Cancer Research, London, UK.en_GB
dc.identifier.journalOncogeneen_GB
html.description.abstractThe RAF proteins are cytosolic protein kinases that regulate cell responses to extracellular signals. There are three RAF proteins in cells, ARAF, BRAF and CRAF, and recent studies have shown that the formation of complexes by these different isoforms has an important role in their activation, particularly in response to RAF inhibitors. Here, we investigated the role of ARAF in cancer cell signaling and examined the role of ARAF in mediating paradoxical activation of the MAPK pathway in cells treated with RAF inhibitors. We show that two mutations that occur in ARAF in cancer inactivate the kinase. We also show that ARAF is not functionally redundant with CRAF and cannot substitute for CRAF downstream of RAS. We further show that ARAF binds to and is activated by BRAF and that ARAF also forms complexes with CRAF. Critically, ARAF seems to stabilize BRAF:CRAF complexes in cells treated with RAF inhibitors and thereby regulate cell signaling in a subtle manner to ensure signaling efficiency.


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