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XB-ART-16619
EMBO J 1997 Apr 15;168:1953-60. doi: 10.1093/emboj/16.8.1953.
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Mammalian Raf-1 is activated by mutations that restore Raf signaling in Drosophila.

Cutler RE , Morrison DK .


Abstract
An interaction with the Ras proto-oncogene product is a requirement for Raf-1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras-Raf interaction severely impairs the function of both mammalian (Raf-1) and Drosophila (D-Raf) Raf proteins. In D-Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras-binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf-1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras-Raf-1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf-1, allowing Raf-1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf-1, it also abolishes the ability of wild-type Raf-1 to become activated by Ras. This mutation occurs in the cysteine-rich domain (CRD) of Raf-1 and demonstrates the importance of this region for a productive Ras-Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf-1 activity by introducing a novel phosphorylation site into the L12 activation loop of the Raf-1 kinase domain.

PubMed ID: 9155021
PMC ID: PMC1169798
Article link: EMBO J


Species referenced: Xenopus
Genes referenced: esco2 raf1

References [+] :
Alessi, Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. 1994, Pubmed