Rheb inhibits C-raf activity and B-raf/C-raf heterodimerization.

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.
Mesh Terms:
Cell Line, Dimerization, Gene Expression Regulation, Humans, Monomeric GTP-Binding Proteins, Neuropeptides, Phosphorylation, Protein Structure, Tertiary, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-raf, Serine, Signal Transduction, Sirolimus
J. Biol. Chem.
Date: Sep. 01, 2006
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