Impaired binding of 14-3-3 to C-RAF in Noonan syndrome suggests new approaches in diseases with increased Ras signaling.

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.

journal_name

Mol Cell Biol

authors

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

doi

10.1128/MCB.01636-09

subject

Has Abstract

pub_date

2010-10-01 00:00:00

pages

4698-711

issue

19

eissn

0270-7306

issn

1098-5549

pii

MCB.01636-09

journal_volume

30

pub_type

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