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Karbowniczek M , Robertson GP , Henske EP
Rheb inhibits C-Raf activity and B-Raf/C-Raf heterodimerization
J Biol Chem. 2006 Jun 27;281(35) :25447-56
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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 (TSC2) 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 S446 and S338, respectively, concomitant with a decrease in the activities of both kinases and decreased heterodimerization of B-Raf and C-Raf. Importantly, Rheb's impact on B-Raf/C-Raf heterodimerization and kinase activity are Rapamycin insensitive, indicating that they are independent of Rheb's activation of the mTOR/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.
Dk 51052/dk/niddk Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States