Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinasein regulation of cell motility

The coordinated interplay of substrate adhesion and deadhesion is necessary for cell motility. Using MCF-7 cells, we found that insulin-like growth fa ctor 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 acti vation of different integrins. On the other hand, IGF-I promotes the associ ation of insulin receptor substrate 1 with the focal adhesion kinase (FAK), paxillin, and the tyrosine phosphatase SHP-2, resulting in FAK and paxilli n dephosphorylation. Abrogation of SHP-2 catalytic activity with a dominant -negative mutant (SHP2-C>S) abolishes IGF-I-induced FAK dephosphorylation, and cells expressing SHPZ-C>S show reduced IGF-I-stimulated chemotaxis comp ared with either mock- or SHP-2 wild-type-transfected cells. This impairmen t of cell migration is recovered by reintroduction of a catalytically activ e SHP-2. Interestingly, SHP-2-C> S cells show a larger number of focal adhe sion contacts than wild-type cells, suggesting that SHP-2 activity particip ates in the integrin deactivation process. Although SHP-2 regulates mitogen -activated protein kinase activity, the mitogen-activated protein kinase ki nase 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 oth er chemotactic agents and integrins is discussed.