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Publication Abstract from PubMed

The Ras-RAF-MAPK pathway is overactive in many cancers and in some developmental disorders. In one of the latter, Noonan syndrome, nine activating C-RAF mutations cluster around Ser(259), a regulatory site for inhibition by 14-3-3 proteins. We show that these mutations impair binding of 14-3-3 proteins to C-RAF and alter its subcellular localization by promoting Ras-mediated plasma membrane recruitment of C-RAF. By providing biophysical binding data, the 14-3-3/C-RAFpS(259) crystal structure, and cellular analyses we present a mechanistic link between a well-described human developmental disorder and the impairment of a 14-3-3/target protein interaction. As a broader implication of these findings, modulating the C-RAFSer(259)/14-3-3 protein-protein interaction with a stabilizing small molecule may yield a novel potential approach for diseases resulting from an overactive Ras-RAF-MAPK pathway.

Impaired binding of 14-3-3 to C-RAF in Noonan Syndrome implies new approaches in diseases with increased Ras signaling.,Molzan M, Schumacher B, Ottmann C, Baljuls A, Polzien L, Weyand M, Thiel P, Rose R, Rose M, Kuhenne P, Kaiser M, Rapp UR, Kuhlmann J, Ottmann C Mol Cell Biol. 2010 Aug 2. PMID:20679480^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.