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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

Modzelewska, Katarzyna and Elgort, Marc G. and Huang, Jingyu and Jongeward, Gregg and Lauritzen, Amara and Yoon, Charles H. and Sternberg, Paul W. and Moghal, Nadeem (2007) 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. Molecular and Cellular Biology, 27 (10). pp. 3695-3707. ISSN 0270-7306. PMCID PMC1899997.

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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.

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Sternberg, Paul W.0000-0002-7699-0173
Additional Information:© 2007, American Society for Microbiology. Received 1 September 2006/ Returned for modification 7 November 2006/ Accepted 15 February 2007 / Published ahead of print on 5 March 2007. We thank Ben Neel for the hSOS1 cDNA clone and the hemagglutinin (HA)-ERK1 expression vector, Steve Lessnick for HEK 293 EBNA cells and polyethylenimine, and David Virshup for NIH 3T3 cells. We also thank Steve Lessnick, Don Ayer, Scott Kuwada, and members of the Moghal laboratory for critically reading the manuscript and Tommy Wong and Suzanne Elgort for help with figures. We also thank the reviewers for their insightful comments/criticisms about the manuscript. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). We thank the C. elegans Reverse Genetics Core Facility at the University of British Columbia, which is part of the International C. elegans Gene Knockout Consortium, for providing the rac-2(ok326) deletion mutant. This research was supported by Public Health Services grant R01 GM073184 from the National Institutes of Health to N.M. and the Howard Hughes Medical Institute, for which P.W.S. is an Investigator.
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NIHR01 GM073184
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:10
PubMed Central ID:PMC1899997
Record Number:CaltechAUTHORS:MODmcb07
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ID Code:8378
Deposited By: Archive Administrator
Deposited On:02 Aug 2007
Last Modified:02 Oct 2019 23:50

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