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Papers In Press, published online ahead of print February 11, 2003
J. Biol. Chem, 10.1074/jbc.M210670200
Submitted on October 18, 2002
Revised on February 5, 2003
Accepted on February 11, 2003

Development of an efficient 'substrate trapping' mutant of SHP2, and identification of EGFR, Gab1 and three other proteins as target substrates

Yehenew M. Agazie and Michael J. Hayman

Molecular Genetics and Microbiology, SUNY@Stony Brook, Stony Brook, NY 11794-5222

Corresponding Author: mhayman{at}ms.cc.sunysb.edu

Src homology 2 containing phosphotyrosine phosphatase (SHP2) is a positive effector of growth factor, cytokine and integrin signaling. However, neither its physiological substrate(s) nor its mechanism of action in tyrosine kinase signaling has been demonstrated. We reasoned that 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 (DM protein). The DM protein identified the Epidermal Growth Factor Receptor (EGFR), Grb2 binder 1 (Gab1) 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.


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