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An Activating Mutation in sos-1 Identifies Its Dbl Domain as a Critical Inhibitor of the Epidermal Growth Factor Receptor Pathway during Caenorhabditis elegans Vulval Development

Katarzyna Modzelewska,^1, Marc G. Elgort,^1, Jingyu Huang,¹ Gregg Jongeward,^2, Amara Lauritzen,¹ Charles H. Yoon,^2, Paul W. Sternberg,² and Nadeem Moghal^1*

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Room 3242, Salt Lake City, Utah 84112-5550,¹ Howard Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, California 91125²

Received 1 September 2006/ Returned for modification 7 November 2006/ Accepted 15 February 2007

Proper regulation of receptor tyrosine kinase (RTK)-Ras-mitogen-activated protein kinase (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 Caenorhabditis elegans SOS-1 that promotes epidermal growth factor receptor (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, activates the MAPK pathway by disrupting an autoinhibitory function of the Dbl domain on Ras activation. Our work suggests that functionally similar point mutations in humans could directly contribute to disease.

Published ahead of print on 5 March 2007.

K. Modzelewska and M. G. Elgort contributed equally.

Present address: Department of Biological Sciences, University of the Pacific, 3601 Pacific Ave., Stockton, CA 95211.

Present address: Department of Surgery, Columbia Presbyterian Medical Center, 177 Fort Washington Avenue, New York, NY 10032.