PTPα regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration

e investigated the molecular and cellular actions of receptor protein tyrosine phosphatase (PTP) alpha in integrin signaling using immortalized fibroblasts derived from wild-type and PTPalpha-deficient mouse embryos. Defects in PTPalpha(-/-) migration in a wound healing assay were associated with altered cell shape and focal adhesion kinase (FAK) phosphorylation. The reduced haptotaxis to fibronectin (FN) of PTPalpha(-/-) cells was increased by expression of active (but not inactive) PTPalpha. Integrin-mediated formation of src-FAK and fyn-FAK complexes was reduced or abolished in PTPalpha(-/-) cells on FN, concomitant with markedly reduced phosphorylation of FAK at Tyr397. Reintroduction of active (but not inactive) PTPa restored FAK Tyr-397 phosphorylation. FN-induced cytoskeletal rearrangement was retarded in PTPalpha(-/-) cells, with delayed filamentous actin stress fiber assembly and focal adhesion formation. This mimicked the effects of treating wild-type fibroblasts with the src family protein tyrosine kinase (Src-PTK) inhibitor PP2. These results, together with the reduced src/fyn tyrosine kinase activity in PTPalpha(-/-) fibroblasts (Ponniah et al., 1999; Su et al., 1999), suggest that PTPalpha functions in integrin signaling and cell migration as an Src-PTK activator. Our paper establishes that PTPalpha is required for early integrin-proximal events, acting upstream of FAK to affect the timely and efficient phosphorylation of FAK Tyr-397.