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J. Biol. Chem., Vol. 281, Issue 35, 25447-25456, September 1, 2006

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Rheb Inhibits C-Raf Activity and B-Raf/C-Raf Heterodimerization^*

Magdalena Karbowniczek, Gavin P. Robertson, and Elizabeth Petri Henske¹

From the Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 and the Pharmacology Department, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033

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.

Received for publication, June 1, 2006 , and in revised form, June 23, 2006.

^* This work was supported by National Institutes of Health Grant DK 51052, The LAM Foundation (Cincinnati, OH), and The Rothberg Foundation for Childhood Diseases (Guilford, CT). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111. Tel.: 215-728-2428; Fax: 215-214-1623; E-mail: Elizabeth.Henske{at}fccc.edu.

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