Phosphorylated α-actinin and protein-tyrosine phosphatase 1B coregulate the disassembly of the focal adhesion kinase·Src complex and promote cell migration

The focal adhesion kinase (FAK) is a key regulator of cell migration. Phosphorylation at Tyr-397 activates FAK and creates a binding site for Src family kinases. FAK phosphorylates the cytoskeletal protein α-actinin at Tyr-12. Here we report that protein-tyrosine phosphatase 1B (PTP 1B) is an α-actinin phosphatase. PTP 1B-dependent dephosphorylation of α-actinin was seen in COS-7 cells and PTP 1B-null fibroblasts reconstituted with PTP 1B. Furthermore, we show that coexpression of wild-type α-actinin and PTP 1B causes dephosphorylation at Tyr-397 in FAK. No dephosphorylation was observed in cells coexpressing the α-actinin phosphorylation mutant Y12F and PTP 1B. Furthermore, the phosphorylation at four other sites in FAK was not altered by PTP 1B. In addition, we found that phosphorylated α-actinin bound to Src and reduced the binding of FAK to Src. The dephosphorylation at Tyr-397 in FAK triggered by wild-type α-actinin and PTP 1B caused a significant increase in cell migration. We propose that phosphorylated α-actinin disrupts the FAK·Src complex exposing Tyr-397 in FAK to PTP 1B. These findings uncover a novel feedback loop involving phosphorylated α-actinin and PTP 1B that regulates FAK·Src interaction and cell migration.