The PP2A-associated protein α4 plays a critical role in the regulation of cell spreading and migration

Compared with kinases, the role of protein phosphatases in regulating biological functions is less well understood. Here we show that α4, 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 α4 were impaired in their ability to spread and migrate compared with wild-type cells, whereas enforced expression of α4 promoted cell spreading and migration. These effects were not restricted to fibroblasts. Using a T cell-specific α4 transgenic mouse model, increased α4 expression was found to increase lymphocyte motility and chemotaxis. Elevated α4 expression results in an increase in the GTP-bound state of Rac1, and GTP-bound Rac1 was dramatically reduced in α4-deficient cells. A constitutively active mutant of Rac1 rescued the defects of cell spreading and migration caused by α4 deletion, while inhibition of Rac1 blocked the ability of α4 to promote cell migration. Together, these data define a novel role for the protein phosphatase 2A regulatory subunit α4 in the regulation of cell spreading and migration.