TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival

• Published in: The international journal of biochemistry & cell biology Vol. 41; no. 5; pp. 1102 - 1115
• Main Authors: Lambert, Elise, Bridoux, Lucie, Devy, Jérôme, Dassé, Emilie, Sowa, Marie-Line, Duca, Laurent, Hornebeck, William, Martiny, Laurent, Petitfrère-Charpentier, Emmanuelle
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.05.2009; Elsevier
• Subjects: Apoptosis - physiology; CD44; Cell Line, Tumor; Cell Membrane - enzymology; Cell Membrane - metabolism; Cell Survival - physiology; Cells, Cultured; Enzyme Inhibitors - pharmacology; Enzyme Precursors - antagonists & inhibitors; Enzyme Precursors - biosynthesis; Enzyme Precursors - genetics; Enzyme Precursors - metabolism; Erythroid cell survival; Erythroid Cells - cytology; Erythroid Cells - drug effects; Erythroid Cells - metabolism; Humans; Hyaluronan Receptors - biosynthesis; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors; proMMP-9; Receptor; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Signal Transduction; TIMP-1; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tissue Inhibitor of Metalloproteinase-1 - pharmacology; Erythroid cell survival; MMP; proMMP-9; TIMP-1; Receptor; CD44
• ISSN: 1357-2725; 1878-5875; 1878-5875
• DOI: 10.1016/j.biocel.2008.10.017

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.