A New alpha5beta1 integrin-dependent survival pathway through GSK3beta 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 beta (GSK3beta) is a new pathway supporting the chemoresistance of leukemic cells adhered to fibronectin.


RESULTS
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 GSK3beta through Ser-9 dephosphorylation in adherent U937 cells. The GSK3beta-dependent survival pathway occurred in adherent leukemic cells from patients but not in the HL-60 and KG1 cell lines. In adhesion, activated GSK3beta 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 GSK3beta. In adherent leukemic cells, alpha(5)beta(1) integrin but not alpha(4)beta(1) upregulated the resistance to TNFalpha-induced apoptosis. Both extrinsic and intrinsic apoptotic pathways were under the control of alpha(5)beta(1) and GSK3beta.


CONCLUSIONS
Our data show that, upon serum starvation, alpha(5)beta(1) integrin engagement could regulate specific pro-survival functions through the activation of GSK3beta.
De Toni-Costes
Fabienne
F
Unité 563, Institut National des Sciences et de la Recherche Médicale, Toulouse, France.
Despeaux
Mathieu
M
Bertrand
Jessica
J
Bourogaa
Ezzeddine
E
Ysebaert
Loïc
L
Payrastre
Bernard
B
Racaud-Sultan
Claire
C
D017209:Apoptosis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D005353:Fibronectins / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018922:HL-60 Cells; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics* / Q000378:metabolism; D007938:Leukemia / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D020298:U937 Cells
D005353:Fibronectins; D039081:Integrin alpha5beta1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2