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

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... d 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. . 3 The abbreviations used are: PP2A, protein phosphatase 2A; MEF, mouse embryonic fibroblast; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; FN, fibronectin; SDF, stromal cell-derived factor; FITC, fluorescein isothiocyanate; GFP, green fluorescence protein; TOR, target of rapamycin; ER, estrogen receptor. 4 M. Kong, unpublished data.