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Originally published In Press as doi:10.1074/jbc.M110547200 on January 4, 2002

J. Biol. Chem., Vol. 277, Issue 11, 9498-9504, March 15, 2002
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Regulation of the Mitogen-activated Protein Kinase Signaling Pathway by SHP2*

Jess M. CunnickDagger §, Songshu MengDagger §, Yuan RenDagger §, Caroline DespontsDagger §, Hong-Gang WangDagger §, Julie Y. DjeuDagger §, and Jie WuDagger §||**

From the Dagger  H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612 and the § Department of Interdisciplinary Oncology,  Institute for Biomolecular Science, and || Department of Medical Microbiology and Immunology, University of South Florida, Tampa, Florida 33612

Gab1-SHP2 association is required for Erk mitogen-activated protein kinase activation by several growth factors. Gab1-SHP2 interaction activates SHP2. However, an activated SHP2 still needs to associate with Gab1 to mediate Erk activation. It was unclear whether SHP2 is required to dephosphorylate a negative phosphorylation site on Gab1 or whether SHP2 needs the Gab1 pleckstrin homology (PH) domain to target it to the plasma membrane. We found that expression of a fusion protein consisting of the Gab1 PH domain and an active SHP2 (Gab1PH-SHP2Delta N) induced constitutive Mek1 and Erk2 activation. Linking the active SHP2Delta N to the PDK1 PH domain or the FRS2beta myristoylation sequence also induced Mek1 activation. Mek1 activation by Gab1PH-SHP2Delta N was inhibited by an Src inhibitor and by Csk. Significantly, Gab1PH-SHP2Delta N induced Src activation. Gab1PH-SHP2Delta N expression activated Ras, and the Gab1PH-SHP2Delta N-induced Mek1 activation was blocked by RasN17. These findings suggest that Gab1PH-SHP2Delta N activated a signaling step upstream of Src and Ras. The SHP2 tyrosine phosphatase activity is essential for the function of the fusion protein. Together, these data show that the Gab1 sequence, besides the PH domain and SHP2 binding sites, is dispensable for Erk activation, suggesting that the primary role of Gab1 association with an activated SHP2 is to target it to the membrane.

* This work was supported by Grant RPG0028901TBE from the American Cancer Society and by Grant CA77467 from the National Institutes of Health.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.

** To whom correspondence should be addressed: Molecular Oncology Program, MRC 3-East, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612. Tel.: 813-979-6713; Fax: 813-903-6817; E-mail: wu@moffitt.usf.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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