A New α(5)β(1) Integrin-Dependent Survival Pathway Through GSK3β Activation in Leukemic Cells

BACKGROUND: Cell survival mediated by integrin engagement has been implicated in cell adhesion-mediated drug resistance. We have recently demonstrated that the activation of glycogen synthase kinase 3 β (GSK3β) is a new pathway supporting the chemoresistance of leukemic cells adhered to fibronectin. METHODOLOGY AND PRINCIPAL FINDINGS: We show here that in conditions of serum starvation, the fibronectin receptor α(5)β(1) integrin, but not α(4)β(1), induced activation of GSK3β through Ser-9 dephosphorylation in adherent U937 cells. The GSK3β-dependent survival pathway occurred in adherent leukemic cells from patients but not in the HL-60 and KG1 cell lines. In adhesion, activated GSK3β was found in the cytosol/plasma membrane compartment and was co-immunoprecipitated with α(5) integrin, the phosphatase PP2A and the scaffolding protein RACK1. PP2A and its regulatory subunit B' regulated the Ser-9 phosphorylation of GSK3β. In adherent leukemic cells, α(5)β(1) integrin but not α(4)β(1) upregulated the resistance to TNFα-induced apoptosis. Both extrinsic and intrinsic apoptotic pathways were under the control of α(5)β(1) and GSK3β. CONCLUSIONS AND SIGNIFICANCE: Our data show that, upon serum starvation, α(5)β(1) integrin engagement could regulate specific pro-survival functions through the activation of GSK3β.