Molzan, Manuela; Schumacher, Benjamin; Ottmann, Corinna; Baljuls, Angela; Polzien, Lisa; Weyand, Michael; Thiel, Philipp; Rose, Rolf; Rose, Micheline; Kuhenne, Philipp; Kaiser, Markus; Rapp, Ulf R.; Kuhlmann, Jürgen; Ottmann, Christian:
Impaired Binding of 14-3-3 to C-RAF in Noonan Syndrome Suggests New Approaches in Diseases with Increased Ras Signaling
2010
In: Molecular and cellular biology : MCB, Jg. 30 (2010), Heft 19, S. 4698 - 4711
Artikel/Aufsatz in Zeitschrift / Fach: Biologie
Fakultät für Biologie
Titel:
Impaired Binding of 14-3-3 to C-RAF in Noonan Syndrome Suggests New Approaches in Diseases with Increased Ras Signaling
Autor(in):
Molzan, Manuela; Schumacher, Benjamin; Ottmann, Corinna; Baljuls, Angela; Polzien, Lisa; Weyand, Michael im Online-Personal- und -Vorlesungsverzeichnis LSF anzeigen; Thiel, Philipp; Rose, Rolf; Rose, Micheline; Kuhenne, Philipp im Online-Personal- und -Vorlesungsverzeichnis LSF anzeigen; Kaiser, Markus im Online-Personal- und -Vorlesungsverzeichnis LSF anzeigen; Rapp, Ulf R.; Kuhlmann, Jürgen; Ottmann, Christian
Erscheinungsjahr:
2010
Erschienen in:
Molecular and cellular biology : MCB, Jg. 30 (2010), Heft 19, S. 4698 - 4711
ISSN:
Link URL:

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 Ser259, 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-RAFpS259 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-RAFSer259/14-3-3 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.