Concerted Activity of Tyrosine Phosphatase SHP-2 and Focal Adhesion Kinase in Regulation of Cell Motility

Author:

Mañes Santos1,Mira Emilia1,Gómez-Mouton Concepción1,Zhao Zhizuang Joe2,Lacalle Rosa Ana1,Martínez-A. Carlos1

Affiliation:

1. Department of Immunology and Oncology, Centro Nacional de Biotecnologı́a, Consejo Superior de Investigaciones Cientı́ficas,Universidad Autónoma de Madrid, Campus de Cantoblanco, E-28049 Madrid, Spain, 1 and

2. Hematology/Oncology Division, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232-63052

Abstract

ABSTRACT The coordinated interplay of substrate adhesion and deadhesion is necessary for cell motility. Using MCF-7 cells, we found that insulin-like growth factor I (IGF-I) induces the adhesion of MCF-7 to vitronectin and collagen in a dose- and time-dependent manner, suggesting that IGF-I triggers the activation of different integrins. On the other hand, IGF-I promotes the association of insulin receptor substrate 1 with the focal adhesion kinase (FAK), paxillin, and the tyrosine phosphatase SHP-2, resulting in FAK and paxillin dephosphorylation. Abrogation of SHP-2 catalytic activity with a dominant-negative mutant (SHP2-C>S) abolishes IGF-I-induced FAK dephosphorylation, and cells expressing SHP2-C>S show reduced IGF-I-stimulated chemotaxis compared with either mock- or SHP-2 wild-type-transfected cells. This impairment of cell migration is recovered by reintroduction of a catalytically active SHP-2. Interestingly, SHP-2-C>S cells show a larger number of focal adhesion contacts than wild-type cells, suggesting that SHP-2 activity participates in the integrin deactivation process. Although SHP-2 regulates mitogen-activated protein kinase activity, the mitogen-activated protein kinase kinase inhibitor PD-98059 has only a marginal effect on MCF-7 cell migration. The role of SHP-2 as a general regulator of cell chemotaxis induced by other chemotactic agents and integrins is discussed.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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