Integrin-induced Tyrosine Phosphorylation of Protein-tyrosine Phosphatase-α Is Required for Cytoskeletal Reorganization and Cell Migration

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