ARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers

Oncogene. 2013 Jun 27;32(26):3207-12. doi: 10.1038/onc.2012.330. Epub 2012 Aug 27.

Abstract

The 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Enzyme Activation
  • Humans
  • MAP Kinase Signaling System / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Protein Isoforms
  • Protein Multimerization
  • Proto-Oncogene Proteins B-raf / chemistry*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins c-raf / metabolism*
  • Signal Transduction
  • raf Kinases / antagonists & inhibitors
  • raf Kinases / chemistry*
  • raf Kinases / genetics
  • raf Kinases / metabolism

Substances

  • Protein Isoforms
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • raf Kinases
  • Mitogen-Activated Protein Kinases