Impaired binding of 14-3-3 to C-RAF in noonan syndrome suggests new approaches in diseases with increased ras signaling

M. Molzan, B. Schumacher, C. Ottmann, A. Baljuls, L. Polzien, M. Weyand, P. Thiel, R. Rose, M. Rose, P. Kuhenne, M. Kaiser, U.R. Rapp, J. Kuhlmann, C. Ottmann

Research output: Contribution to journalArticleAcademicpeer-review

75 Citations (Scopus)

Abstract

The Ras-RAF-mitogen-activated protein kinase (Ras-RAF-MAPK) pathway is overactive in many cancers and in some developmental disorders. In one of those disorders, namely, 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 presenting biophysical binding data, the 14-3-3/C-RAFpS(259) crystal structure, and cellular analyses, we indicate 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 treatment of diseases resulting from an overactive Ras-RAF-MAPK pathway.
Original languageEnglish
Pages (from-to)4698-4711
Number of pages14
JournalMolecular and cellular biology
Volume30
Issue number19
DOIs
Publication statusPublished - 2010

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