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Originally published In Press as doi:10.1074/jbc.M210670200 on February 11, 2003

J. Biol. Chem., Vol. 278, Issue 16, 13952-13958, April 18, 2003
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Development of an Efficient "Substrate-trapping" Mutant of Src Homology Phosphotyrosine Phosphatase 2 and Identification of the Epidermal Growth Factor Receptor, Gab1, and Three Other Proteins as Target Substrates*

Yehenew M. Agazie and Michael J. HaymanDagger

From the Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York, 11794-5222

Src homology containing phosphotyrosine phosphatase 2 (SHP2) is a positive effector of growth factor, cytokine, and integrin signaling. However, neither its physiological substrate nor its mechanism of action in tyrosine kinase signaling has been demonstrated. We reasoned that the identification of physiological substrates of SHP2 would be a stepping stone in elucidating its mechanism of action, and, thus, we constructed a potent trapping mutant of SHP2. Surprisingly, the frequently used Asp to Ala substitution did not give rise to a trapping mutant. However, we were able to develop an efficient trapping mutant of SHP2 by introducing Asp to Ala and Cys to Ser double mutations. The double mutant (DM) protein identified the epidermal growth factor receptor (EGFR), the Grb2 binder 1, and three other, as yet unidentified, phosphotyrosyl proteins as candidate physiological substrates. Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that EGFR and Gab1 represent physiological SHP2 substrates. Therefore, the DM protein would serve as an important tool in future SHP2 studies, including identification of p190, p150, and p90.

* This work was supported by National Institutes of Health Public Service Grants CA28146 and CA42573 (to M. J. H.).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.

Dagger To whom correspondence should be addressed. Tel.: 631-632-8792; Fax: 631-632-8891; E-mail: mhayman@ms.cc.sunysb.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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