Received for publication April 11, 2006.
Revised May 19, 2006.
Accepted for publication May 22, 2006.

Discovery of a Novel Shp2 Protein Tyrosine Phosphatase Inhibitor

Abstract

Shp2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. It is involved in growth factor-induced activation of mitogen-activated protein (MAP) kinases Erk1 and Erk2 (Erk1/2) and has been implicated in the pathogenicity of the oncogenic bacterium Helicobactor pylori (H. pylori). Moreover, gain-of-function Shp2 mutations have been found in childhood leukemias and Noonan syndrome. Thus, small molecule Shp2 PTP inhibitors are much needed reagents for evaluation of Shp2 as a therapeutic target and for chemical biology studies of Shp2 function. By screening the National Cancer Institute (NCI) Diversity Set chemical library, we identified NSC-87877 as a potent Shp2 PTP inhibitor. Molecular modeling and site-directed mutagenesis studies suggested that NSC-87877 binds to the catalytic cleft of Shp2 PTP. NSC-87877 cross-inhibited Shp1 in vitro, but it was selective for Shp2 over other PTPs (PTP1B, HePTP, DEP1, CD45, and LAR). Importantly, NSC-87877 inhibited EGF-induced activation of Shp2 PTP, Ras, and Erk1/2 in cell cultures but did not block EGF-induced Gab1 tyrosine phosphorylation or Gab1-Shp2 association. Furthermore, NSC-87877 inhibited Erk1/2 activation by a Gab1-Shp2 chimera but did not affect the Shp2-independent Erk1/2 activation by phorbol 12-myristate 13-acetate (PMA). These results identified NSC-87877 as the first PTP inhibitor capable of inhibiting Shp2 PTP in cell cultures without a detectable off-target effect. Our study also provides the first pharmacological evidence that Shp2 mediates EGF-induced Erk1/2 MAP kinase activation.

Key words: NGF/EGF, MAP Kinase

This article has been cited by other articles:

				J. A. Wahle, K. H. T. Paraiso, R. D. Kendig, H. R. Lawrence, L. Chen, J. Wu, and W. G. Kerr Inappropriate Recruitment and Activity by the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP1) Is Responsible for Receptor Dominance in the SHIP-Deficient NK Cell J. Immunol., December 15, 2007; 179(12): 8009 - 8015. [Abstract] [Full Text] [PDF]

				Y. G. Langdon, S. C. Goetz, A. E. Berg, J. T. Swanik, and F. L. Conlon SHP-2 is required for the maintenance of cardiac progenitors Development, November 15, 2007; 134(22): 4119 - 4130. [Abstract] [Full Text] [PDF]

				S. P. Manandhar, E. R. Hildebrandt, and W. K. Schmidt Small-Molecule Inhibitors of the Rce1p CaaX Protease J Biomol Screen, October 1, 2007; 12(7): 983 - 993. [Abstract] [PDF]