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 alpha 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 alpha 4 were impaired in their ability to spread and migrate compared with wild-type cells, whereas enforced expression of alpha 4 promoted cell spreading and migration. These effects were not restricted to fibroblasts. Using a T cell-specific alpha 4 transgenic mouse model, increased alpha 4 expression was found to increase lymphocyte motility and chemotaxis. Elevated alpha 4 expression results in an increase in the GTP-bound state of Rac1, and GTP-bound Rac1 was dramatically reduced in alpha 4-deficient cells. A constitutively active mutant of Rac1 rescued the defects of cell spreading and migration caused by alpha 4 deletion, while inhibition of Rac1 blocked the ability of alpha 4 to promote cell migration. Together, these data define a novel role for the protein phosphatase 2A regulatory subunit alpha 4 in the regulation of cell spreading and migration.