Novel Recognition Motif on Fibroblast Growth Factor Receptor Mediates Direct Association and Activation of SNT Adapter Proteins*
- From the ‡Brookdale Center for Developmental and Molecular Biology and the §Graduate Program in Molecular, Cellular, Biochemical and Developmental Sciences, Mount Sinai School of Medicine, New York, New York 10029
Abstract
Fibroblast growth factors (FGFs) stimulate tyrosine phosphorylation of a membrane-anchored adapter protein, FRS2/SNT-1, promoting its association with Shp-2 tyrosine phosphatase and upstream activators of Ras. Using the yeast two-hybrid protein-protein interaction assay, we show that FRS2/SNT-1 and a newly isolated SNT-2 protein directly bind to FGF receptor-1 (FGFR-1). A juxtamembrane segment of FGFR-1 and the phosphotyrosine-binding domain of SNTs are both necessary and sufficient for interaction in yeast andin vitro, and FGFR-mediated SNT tyrosine phosphorylationin vivo requires these segments of receptor and SNT. Our findings establish SNTs as direct protein links between FGFR-1 and multiple downstream pathways. The SNT binding motif of FGFR-1 is distinct from previously described phosphotyrosine-binding domain recognition motifs, lacking both tyrosine and asparagine residues.
Footnotes
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↵* This work was supported by Research Grant R21-GM55666 (to M. G.) and by Predoctoral Training Grant T32-GM08553 (to K. W. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵¶ These authors contributed equally to this work.
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↵‖ To whom correspondence should be addressed: Brookdale Center for Developmental and Molecular Biology, Box 1126, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029. Tel.: 212-241-3394; Fax: 212-860-9279; E-mail:mgoldfa{at}smtplink.mssm.edu.
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↵1 The abbreviations used are: RTK, receptor with intrinsic tyrosine kinase activity; SH2, Src homology-2; PTB, phosphotyrosine-binding; EGF, epidermal growth factor; EGFR, EGF receptor; PLCγ, phospholipase C-γ; IR, insulin receptor; IRS, insulin receptor substrate; FGF, fibroblast growth factor; FGFR, FGF receptor; BD, binding domain; AD, activation domain; GST, glutathioneS-transferase; WT, wild type; IP, immunoprecipitation; PY, phosphotyrosine.
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↵2 H. Xu and M. Goldfarb, manuscript in preparation.
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↵3 H. Xu and M. Goldfarb, unpublished data.
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- Received April 13, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
