Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / physiology
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Cell Line, Tumor
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Cell Membrane / enzymology
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Cell Membrane / metabolism
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Cell Survival / physiology
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Cells, Cultured
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Enzyme Inhibitors / pharmacology
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Enzyme Precursors / antagonists & inhibitors
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Enzyme Precursors / biosynthesis
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Enzyme Precursors / genetics
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Enzyme Precursors / metabolism*
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Erythroid Cells / cytology
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Erythroid Cells / drug effects
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Erythroid Cells / metabolism*
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Humans
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Hyaluronan Receptors / biosynthesis
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism*
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Matrix Metalloproteinase 9 / biosynthesis
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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Matrix Metalloproteinase Inhibitors
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Signal Transduction
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-1 / metabolism*
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Tissue Inhibitor of Metalloproteinase-1 / pharmacology
Substances
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CD44 protein, human
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Enzyme Inhibitors
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Enzyme Precursors
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Hyaluronan Receptors
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Matrix Metalloproteinase Inhibitors
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RNA, Messenger
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Recombinant Proteins
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Tissue Inhibitor of Metalloproteinase-1
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pro-matrix metalloproteinase 9
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Matrix Metalloproteinase 9