Integrin-induced tyrosine phosphorylation of protein-tyrosine phosphatase-α is required for cytoskeletal reorganization and cell migration

Protein-tyrosine phosphatase-alpha (PTP alpha) activates Src family kinases (SFKs) to promote the integrin-stimulated early autophosphorylation of focal adhesion kinase (FAK). We report here that integrin stimulation induces tyrosine phosphorylation of PTP alpha. PTP alpha was dephosphorylated upon fibroblast detachment from the substratum and rephosphorylated when cells were plated on the integrin ligand fibronectin. PTP alpha phosphorylation occurred at Tyr(789) and required SFKs ( Src or Fyn/Yes), FAK, and an intact cytoskeleton. It also required active PTP alpha or constitutively active Src. These observations indicate that PTP alpha activates SFKs and that the subsequently activated SFK . FAK tyrosine kinase complex in turn phosphorylates PTP alpha. Reintroduction of wild-type PTP alpha or unphosphorylatable PTP alpha(Y789F) ( but not inactive PTP alpha) into PTP alpha-null fibroblasts restored defective integrin-induced SFK activation, FAK phosphorylation, and paxillin phosphorylation. PTP alpha( Y789F) and inactive PTP alpha could not rescue delayed actin stress fiber assembly and focal adhesion formation or defective cell migration. This study distinguishes two roles of PTP alpha in integrin signaling: an early role as an activator of SFKs and FAK with no requirement for PTP alpha phosphorylation and a later downstream role in cytoskeleton-associated events for which PTP alpha phosphorylation at Tyr(789) is essential.