Journal
CELLULAR SIGNALLING
Volume 19, Issue 6, Pages 1279-1289Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2007.01.013
Keywords
Sin1; Ras; pleckstrin homology; RBD; domain; JNK; Akt; ERK1/2
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Human Sin1 (SAPK-interacting protein 1) is a member of a conserved family of orthologous proteins that have an essential role in signal transduction in yeast and Dictyostelium. This study demonstrates that most Sin I orthologues contain both a Raf-like Ras-binding domain (RBD) and a pleckstrin homology (PH) domain. These domains are functional in the human Sin1 protein, with the PH domain involved in lipid and membrane binding by SinI, and the RBD able to bind activated H-and K-Ras. Sin1 and Ras co-immunoprecipitated and co-localised, showing that these proteins associate with each other in vivo. Overexpression of Sin I inhibited the activation of ERK, Akt and JNK signalling pathways by Ras. In contrast, siRNA knockdown of endogenous Sin1 protein expression in HEK293 cells enhanced the activation of ERK1/2 by Ras. These data suggest that SinI is a mammalian Ras-inhibitor. (c) 2007 Elsevier Inc. All rights reserved.
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