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J. Biol. Chem., Vol. 282, Issue 40, 29712-29720, October 5, 2007

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The PP2A-associated Protein 4 Plays a Critical Role in the Regulation of Cell Spreading and Migration^*

Mei Kong¹, Thi V. Bui, Dara Ditsworth, Josh J. Gruber, Dmitry Goncharov^¶, Vera P. Krymskaya^¶, Tullia Lindsten^||, and Craig B. Thompson²

From the Abramson Family Cancer Research Institute, Department of Cancer Biology, ^¶Pulmonary, Allergy, and Critical Care Division, ^||Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Compared with kinases, the role of protein phosphatases in regulating biological functions is less well understood. Here we show that 4, a non-catalytic subunit of the protein phosphatase 2A, plays a major role in the control of cell spreading, migration, and cytoskeletal architecture. Fibroblasts lacking 4 were impaired in their ability to spread and migrate compared with wild-type cells, whereas enforced expression of 4 promoted cell spreading and migration. These effects were not restricted to fibroblasts. Using a T cell-specific 4 transgenic mouse model, increased 4 expression was found to increase lymphocyte motility and chemotaxis. Elevated 4 expression results in an increase in the GTP-bound state of Rac1, and GTP-bound Rac1 was dramatically reduced in 4-deficient cells. A constitutively active mutant of Rac1 rescued the defects of cell spreading and migration caused by 4 deletion, while inhibition of Rac1 blocked the ability of 4 to promote cell migration. Together, these data define a novel role for the protein phosphatase 2A regulatory subunit 4 in the regulation of cell spreading and migration.

Received for publication, April 13, 2007 , and in revised form, August 3, 2007.

^* This work was supported in part by a grant from the NCI, National Institutes of Health (to C. B. T.). 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 Recipient of a postdoctoral fellowship from the Leukemia and Lymphoma Society and American Association for Cancer Research.

² To whom correspondence should be addressed: Abramson Family Cancer Research Inst., 450 BRBII/III, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-746-5515; Fax: 215-746-5511; E-mail: craig{at}mail.med.upenn.edu.

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