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Molecular and Cellular Biology, March 2000, p. 1526-1536, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Molecular Mechanism for the Shp-2 Tyrosine Phosphatase Function in Promoting Growth Factor Stimulation of Erk Activity

Zhong-Qing Shi,1 De-Hua Yu,1 Morag Park,2 Mark Marshall,1,dagger and Gen-Sheng Feng1,*

Department of Biochemistry and Molecular Biology and Walther Oncology Center, Indiana University School of Medicine and Walther Cancer Institute, Indianapolis, Indiana 46202-5254,1 and Departments of Medicine, Oncology, and Biochemistry, Molecular Oncology Group, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada H3A 1A12

Received 13 August 1999/Returned for modification 15 September 1999/Accepted 23 November 1999

We have previously shown that activation of extracellular signal-regulated kinase (Erk) by epidermal growth factor (EGF) treatment was significantly decreased in mouse fibroblast cells expressing a mutant Shp-2 molecule lacking 65 amino acids in the SH2-N domain, Shp-2Delta 46-110. To address the molecular mechanism for the positive role of Shp-2 in mediating Erk induction, we evaluated the activation of signaling components upstream of Erk in Shp-2 mutant cells. EGF-stimulated Ras, Raf, and Mek activation was significantly attenuated in Shp-2 mutant cells, suggesting that Shp-2 acts to promote Ras activation or to suppress the down-regulation of activated Ras. Biochemical analyses indicate that upon EGF stimulation, Shp-2 is recruited into a multiprotein complex assembled on the Gab1 docking molecule and that Shp-2 seems to exert its biological function by specifically dephosphorylating an unidentified molecule of 90 kDa in the complex. The mutant Shp-2Delta 46-110 molecule failed to participate in the Gab1-organized complex for dephosphorylation of p90, correlating with a defective activation of the Ras-Raf-Mek-Erk cascade in EGF-treated Shp-2 mutant cells. Evidence is also presented that Shp-2 does not appear to modulate the signal relay from EGF receptor to Ras through the Shc, Grb2, and Sos proteins. These results begin to elucidate the mechanism of Shp-2 function downstream of a receptor tyrosine kinase to promote the activation of the Ras-Erk pathway, with potential therapeutic applications in cancer treatment.

* Corresponding author. Present address: The Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 713-6265. Fax: (858) 713-6274. E-mail: gfeng{at}Burnham.org.

dagger Present address: Lilly Research Laboratories, Indianapolis, IN 46285.

Molecular and Cellular Biology, March 2000, p. 1526-1536, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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