A New alpha(5)beta(1) Integrin-Dependent Survival Pathway Through GSK3 beta Activation in Leukemic Cells

作者：De Toni Costes Fabienne^*; Despeaux Mathieu; Bertrand Jessica; Bourogaa Ezzeddine; Ysebaert Loic; Payrastre Bernard; Racaud Sultan Claire

来源：PLos One, 2010, 5(3): e9807.

DOI：10.1371/journal.pone.0009807

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 beta (GSK3 beta) 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 alpha(5)beta(1) integrin, but not alpha(4)beta(1), induced activation of GSK3 beta through Ser-9 dephosphorylation in adherent U937 cells. The GSK3 beta-dependent survival pathway occurred in adherent leukemic cells from patients but not in the HL-60 and KG1 cell lines. In adhesion, activated GSK3 beta was found in the cytosol/plasma membrane compartment and was co-immunoprecipitated with alpha(5) integrin, the phosphatase PP2A and the scaffolding protein RACK1. PP2A and its regulatory subunit B' regulated the Ser-9 phosphorylation of GSK3 beta. In adherent leukemic cells, alpha(5)beta(1) integrin but not alpha(4)beta(1) upregulated the resistance to TNF alpha-induced apoptosis. Both extrinsic and intrinsic apoptotic pathways were under the control of alpha(5)beta(1) and GSK3 beta.
Conclusions and Significance: Our data show that, upon serum starvation, alpha(5)beta(1) integrin engagement could regulate specific pro-survival functions through the activation of GSK3 beta.

• 出版日期2010-3-23