Nonadherent cells switch to a Rac-mediated, SHIP regulated, Akt activation mode for survival.
Constitutively active Rac stimulates Akt activity in T lymphocytes cultured in suspension. This regulation contrasts with findings obtained in fibroblasts, endothelial or neuronal cells grown on substrate, where Akt stimulation occurs independently of Rac. We now show that V12Rac-mediated stimulation of Akt is not restricted to the hematopoietic lineage but is dependent on the adherence status of the cell. V12Rac-mediated stimulation of Akt as well as molecular association between Rac and Akt occurred exclusively in cells kept in suspension. Stimulation and complex formation are dependent on SHIP but in a manner that differs from its role in dephosphorylation of phosphoinositide lipids. Adherent cells lacking SHIP, but not those lacking PTEN, are able to activate Akt through the Rac pathway. Our data reveal the existence of a bona fide Rac to Akt signaling pathway, tightly regulated by SHIP and operational in suspended cells only. This pathway may point to an alternative survival signal that is called into action when cells lose contact with the substrate and/or with other cells.
Chaigne-Delalande
B
B
European Institute of Chemistry and Biology, University of Bordeaux I, Pessac, France.
Anies
G
G
Kramer
I
I
Genot
E
E
D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002478:Cells, Cultured; D006801:Humans; D047468:Immunoprecipitation; D000072181:Inositol Polyphosphate 5-Phosphatases; D009154:Mutation / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D010716:Phosphatidylinositols; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020744:rac GTP-Binding Proteins