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J. Biol. Chem., Vol. 281, Issue 3, 1746-1754, January 20, 2006

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Phosphorylated -Actinin and Protein-tyrosine Phosphatase 1B Coregulate the Disassembly of the Focal Adhesion Kinase·Src Complex and Promote Cell Migration^*

Zhiyong Zhang1, Siang-Yo Lin1, Benjamin G. Neel, and Beatrice Haimovich2

From the Department of Surgery, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, and the Cancer Institute of New Jersey, New Brunswick, New Jersey 08903 and the Cancer Biology Program, Division of Hematology Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

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 -actinin at Tyr-12. Here we report that protein-tyrosine phosphatase 1B (PTP 1B) is an -actinin phosphatase. PTP 1B-dependent dephosphorylation of -actinin was seen in COS-7 cells and PTP 1B-null fibroblasts reconstituted with PTP 1B. Furthermore, we show that coexpression of wild-type -actinin and PTP 1B causes dephosphorylation at Tyr-397 in FAK. No dephosphorylation was observed in cells coexpressing the -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 -actinin bound to Src and reduced the binding of FAK to Src. The dephosphorylation at Tyr-397 in FAK triggered by wild-type -actinin and PTP 1B caused a significant increase in cell migration. We propose that phosphorylated -actinin disrupts the FAK·Src complex exposing Tyr-397 in FAK to PTP 1B. These findings uncover a novel feedback loop involving phosphorylated -actinin and PTP 1B that regulates FAK·Src interaction and cell migration.

Received for publication, August 31, 2005 , and in revised form, October 31, 2005.

^* This work was supported by Grant HL54104 from the National Institutes of Health (to B. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Clinical Academic Bldg., Rm. 7018, 125 Paterson St., New Brunswick, NJ 08903. Tel.: 732-235-8049; Fax: 732-235-6003; E-mail: haimovic{at}umdnj.edu.

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