TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival.
Fiche publication
Date publication
mai 2009
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DEVY Jérôme, Dr DUCA Laurent, Pr MARTINY Laurent, Pr DEVARENNE-CHARPENTIER Emmanuelle
Tous les auteurs :
Lambert E, Bridoux L, Devy J, Dasse E, Sowa ML, Duca L, Hornebeck W, Martiny L, Petitfrere-Charpentier E
Lien Pubmed
Résumé
Besides its ability to inhibit MMP activity, TIMP-1 exhibits other biological functions. We earlier reported that TIMP-1 induced UT-7 erythroid cell survival through activation of the JAK2/PI 3-kinase/Akt pathway and we now aim to determine whether the TIMP-1 anti-apoptotic effect requires MMP involvement. We first show that proMMP-9 was expressed in UT-7 cells and associated with the cell plasma membrane. Such proMMP-9 localization was crucial for TIMP-1 intracellular signalling since (i) TIMP-1 specifically bound to proMMP-9 and (ii) proMMP-9 silencing abrogated the TIMP-1 effect. We also demonstrated that TIMP-1 anti-apoptotic effect was independent on MMP inhibition since MMP-9 function blocking antibodies as well as a synthetic MMP inhibitor were unable to reproduce TIMP-1 effect. Nevertheless, these compounds prevented TIMP-1 binding to proMMP-9 and subsequently abolished TIMP-1-induced cell survival. We finally demonstrated that CD44 anchored proMMP-9 to the plasma membrane and enabled TIMP-1-mediated signal transduction. Therefore, our results indicate that the anti-apoptotic signalling of TIMP-1 depends on the formation of a ternary complex between TIMP-1, proMMP-9 and CD44 at the UT-7 erythroid cell surface.
Référence
Int J Biochem Cell Biol. 2009 May;41(5):1102-15