Rheb inhibits C-Raf activity and B-Raf/C-Raf heterodimerization

Magdalena Karbowniczek, Gavin P. Robertson, Elizabeth Petri Henske

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

The Ras-Raf-MEK signaling cascade is critical for normal development and is activated in many forms of cancer. We have recently shown that B-Raf kinase interacts with and is inhibited by Rheb, the target of the GTPase-activating domain of the tuberous sclerosis complex 2 gene product tuberin. Here, we demonstrate for the first time that activation of Rheb is associated with decreased B-Raf and C-Raf phosphorylation at residues Ser-446 and Ser-338, respectively, concomitant with a decrease in the activities of both kinases and decreased heterodimerization of B-Raf and C-Raf. Importantly, the impact of Rheb on B-Raf/C-Raf heterodimerization and kinase activity are rapamycin- insensitive, indicating that they are independent of Rheb activation of the mammalian target of rapamycin-Raptor complex. In addition, we found that Rheb inhibits the association of B-Raf with H-Ras. Taken together, these results support a central role of Rheb in the regulation of the Ras/B-Raf/C-Raf/ MEK signaling network.

Original languageEnglish (US)
Pages (from-to)25447-25456
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number35
DOIs
StatePublished - Sep 1 2006

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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