a new α5β1 integrin-dependent survival pathway through gsk3β activation in leukemic cells一个新的α5β1 integrin-dependent通过gsk3β激活在白血病细胞生存途径.pdfVIP

A New a b Integrin-Dependent Survival Pathway 5 1 Through GSK3b Activation in Leukemic Cells 1,2 1,2 1,2 1,2 ¨ Fabienne De Toni-Costes , Mathieu Despeaux , Jessica Bertrand , Ezzeddine Bourogaa , Loıc Ysebaert1,2,3, Bernard Payrastre1,2, Claire Racaud-Sultan1,2* ´ ´ ´ 1 Unite 563, Institut National des Sciences et de la Recherche Medicale, Toulouse, France, 2 Universite Toulouse III Paul-Sabatier, Centre de Physiopathologie de Toulouse ˆ ´ Purpan, Toulouse, France, 3 Centre Hospitalier Universitaire de Toulouse, Hopital Purpan, Service d’Hematologie, Toulouse, France Abstract 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 b (GSK3b) 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 a b 5 1 integrin, but not a b , induced activation of GSK3b through Ser-9 dephosphorylation in adherent U937 cells. The GSK3b- 4 1 dependent survival pathway occurred in adherent leukemic cells from patients but not in the HL-60 and KG1 cell lines. In adhesion, activated GSK3b w