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 Bioljournal_title
Molecular and cellular biologyauthors
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 Cdoi
10.1128/MCB.01636-09subject
Has Abstractpub_date
2010-10-01 00:00:00pages
4698-711issue
19eissn
0270-7306issn
1098-5549pii
MCB.01636-09journal_volume
30pub_type
杂志文章abstract::One of the proteins identified as being involved in ribosome biogenesis by high-throughput studies, a putative P-loop-type kinase termed Fap7 (YDL166c), was shown to be required for the conversion of 20S pre-rRNA to 18S rRNA. However, the mechanism underlying this function has remained unclear. Here we demonstrate tha...
journal_title:Molecular and cellular biology
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