Differential roles of TIMP-4 and TIMP-2 in pro-MMP-2 activation by MT1-MMP.
The tissue inhibitors of metalloproteinases (TIMPs) are specific inhibitors of MMP enzymatic activity. However, TIMP-2 can promote the activation of pro-MMP-2 by MT1-MMP. This process is mediated by the formation of a complex between MT1-MMP, TIMP-2, and pro-MMP-2. Binding of TIMP-2 to active MT1-MMP also inhibits the autocatalytic turnover of MT1-MMP on the cell surface. Thus, under certain conditions, TIMP-2 is a positive regulator of MMP activity. TIMP-4, a close homologue of TIMP-2 also binds to pro-MMP-2 and can potentially participate in pro-MMP-2 activation. We coexpressed MT1-MMP with TIMP-4 and investigated its ability to support pro-MMP-2 activation. TIMP-4, unlike TIMP-2, does not promote pro-MMP-2 activation by MT1-MMP. However, TIMP-4 binds to MT1-MMP inhibiting its autocatalytic processing. When coexpressed with TIMP-2, TIMP-4 competitively reduced pro-MMP-2 activation by MT1-MMP. A balance between TIMP-2 and TIMP-4 may be a critical factor in determining the degradative potential of cells in normal and pathological conditions.
Hernandez-Barrantes
S
S
Department of Pathology, Wayne State University, Detroit, Michigan 48201, USA.
Shimura
Y
Y
Soloway
P D
PD
Sang
Q A
QA
Fridman
R
R
D000818:Animals; D002384:Catalysis; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism*; D005822:Genetic Vectors / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D015151:Immunoblotting; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000502:physiology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000502:physiology*; D014162:Transfection; D014616:Vaccinia virus / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
D004792:Enzyme Precursors; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D011994:Recombinant Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C069860:progelatinase