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Mol. Cell. Biol. doi:10.1128/MCB.01630-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

An activating mutation in sos-1 identifies its Dbl domain as a critical inhibitor of the EGFR pathway during C. elegans vulval development

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Rm 3242 Salt Lake City, UT 84112-5550; Howard Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, California 91125

^* To whom correspondence should be addressed. Email: nadeem.moghal{at}hci.utah.edu.

	Abstract

Proper regulation of receptor tyrosine kinase (RTK)-Ras-MAPK signaling pathways is critical for normal development and the prevention of cancer. SOS is a dual function guanine nucleotide exchange factor (GEF) that catalyzes exchange on Ras and Rac. Although the physiologic role of SOS and its CDC25 domain in RTK-mediated Ras activation is well-established, the in vivo function of its Dbl Rac GEF domain is less clear. We have identified a novel gain-of-function missense mutation in the Dbl domain of C. elegans SOS-1 that promotes EGFR signaling in vivo. Our data indicate that a major developmental function of the Dbl domain is to inhibit EGF-dependent MAPK activation. The amount of inhibition conferred by the Dbl domain is equal to that of established trans-acting inhibitors of the EGFR pathway including c-Cbl and RasGAP, and more than that of MAPK phosphatase. In conjunction with molecular modeling, our data suggest that the C. elegans mutation as well as an equivalent mutation in human SOS1 activate the MAPK pathway by disrupting an auto-inhibitory function of the Dbl domain on Ras activation. Our work suggests that functionally similar point mutations in humans could directly contribute to disease.