The PP2A-associated protein alpha4 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 alpha4, 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 alpha4 were impaired in their ability to spread and migrate compared with wild-type cells, whereas enforced expression of alpha4 promoted cell spreading and migration. These effects were not restricted to fibroblasts. Using a T cell-specific alpha4 transgenic mouse model, increased alpha4 expression was found to increase lymphocyte motility and chemotaxis. Elevated alpha4 expression results in an increase in the GTP-bound state of Rac1, and GTP-bound Rac1 was dramatically reduced in alpha4-deficient cells. A constitutively active mutant of Rac1 rescued the defects of cell spreading and migration caused by alpha4 deletion, while inhibition of Rac1 blocked the ability of alpha4 to promote cell migration. Together, these data define a novel role for the protein phosphatase 2A regulatory subunit alpha4 in the regulation of cell spreading and migration.
Kong
Mei
M
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Bui
Thi V
TV
Ditsworth
Dara
D
Gruber
Josh J
JJ
Goncharov
Dmitry
D
Krymskaya
Vera P
VP
Lindsten
Tullia
T
Thompson
Craig B
CB
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002633:Chemotaxis; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018832:Molecular Chaperones; D009479:Neuropeptides; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology*; D014945:Wound Healing; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
D048868:Adaptor Proteins, Signal Transducing; C092377:Igbp1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009479:Neuropeptides; D010750:Phosphoproteins; C484602:Rac1 protein, mouse; D006160:Guanosine Triphosphate; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein