TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival.
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.
Lambert
Elise
E
URCA, CNRS UMR 6237 (MEDyC), Laboratoire Signalisation et Récepteurs Matriciels, Moulin de Housse, 51687 Reims Cedex 2, France. elise.lambert@univ-reims.fr
Bridoux
Lucie
L
Devy
Jérôme
J
Dassé
Emilie
E
Sowa
Marie-Line
ML
Duca
Laurent
L
Hornebeck
William
W
Martiny
Laurent
L
Petitfrère-Charpentier
Emmanuelle
E
D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D041905:Erythroid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
C497483:CD44 protein, human; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D018960:Hyaluronan Receptors; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9