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Molecular and Cellular Biology, December 2001, p. 8104-8116, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.8104-8116.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Caenorhabditis elegans EGL-15 Signaling Pathway Implicates a DOS-Like Multisubstrate Adaptor Protein in Fibroblast Growth Factor Signal Transduction

Jennifer L. Schutzman, Christina Z. Borland, John C. Newman, Matthew K. Robinson, Michelle Kokel,dagger and Michael J. Stern*

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520-8005

Received 31 January 2001/Returned for modification 9 April 2001/Accepted 18 August 2001

EGL-15 is a fibroblast growth factor receptor in the nematode Caenorhabditis elegans. Components that mediate EGL-15 signaling have been identified via mutations that confer a Clear (Clr) phenotype, indicative of hyperactivity of this pathway, or a suppressor-of-Clr (Soc) phenotype, indicative of reduced pathway activity. We have isolated a gain-of-function allele of let-60 ras that confers a Clr phenotype and implicated both let-60 ras and components of a mitogen-activated protein kinase cascade in EGL-15 signaling by their Soc phenotype. Epistasis analysis indicates that the gene soc-1 functions in EGL-15 signaling by acting either upstream of or independently of LET-60 RAS. soc-1 encodes a multisubstrate adaptor protein with an amino-terminal pleckstrin homology domain that is structurally similar to the DOS protein in Drosophila and mammalian GAB1. DOS is known to act with the cytoplasmic tyrosine phosphatase Corkscrew (CSW) in signaling pathways in Drosophila. Similarly, the C. elegans CSW ortholog PTP-2 was found to be involved in EGL-15 signaling. Structure-function analysis of SOC-1 and phenotypic analysis of single and double mutants are consistent with a model in which SOC-1 and PTP-2 act together in a pathway downstream of EGL-15 and the Src homology domain 2 (SH2)/SH3-adaptor protein SEM-5/GRB2 contributes to SOC-1-independent activities of EGL-15.

* Corresponding author. Mailing address: Yale University School of Medicine, Department of Genetics, SHM I-354, P.O. Box 208005, New Haven, CT 06520-8005. Phone: (203) 737-2283. Fax: (203) 785-6333. E-mail: Michael.Stern{at}Yale.edu.

dagger Present address: The Salk Institute, La Jolla, CA 92037.

Molecular and Cellular Biology, December 2001, p. 8104-8116, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.8104-8116.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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