title: Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion.
abstract: Activation of proMMP-2 by MT1-MMP is considered to be a critical event in cancer cell invasion. In the activation step, TIMP-2 bound to MT1-MMP on the cell surface acts as a receptor for proMMP-2. Subsequently, adjacent TIMP-2-free MT1-MMP activates the proMMP-2 in the ternary complex. In this study, we demonstrate that MT1-MMP forms a homophilic complex through the hemopexin-like (PEX) domain that acts as a mechanism to keep MT1-MMP molecules close together to facilitate proMMP-2 activation. Deletion of the PEX domain in MT1-MMP, or swapping the domain with the one derived from MT4-MMP, abolished the ability to activate proMMP-2 on the cell surface without affecting the proteolytic activities. In addition, expression of the mutant MT1-MMP lacking the catalytic domain (MT1PEX-F) efficiently inhibited complex formation of the full-length enzymes and activation of pro MMP-2. Furthermore, expression of MT1PEX-F inhibited proMMP-2 activation and Matrigel invasion activity of invasive human fibrosarcoma HT1080 cells. These findings elucidate a new function of the PEX domain: regulating MT1-MMP activity on the cell surface, which accelerates cellular invasiveness in the tissue.
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Itoh
authors.forename: A
authors.initials: A
authors.lastname: Takamura
authors.forename: N
authors.initials: N
authors.lastname: Ito
authors.forename: Y
authors.initials: Y
authors.lastname: Maru
authors.forename: H
authors.initials: H
authors.lastname: Sato
authors.forename: N
authors.initials: N
authors.lastname: Suenaga
authors.forename: T
authors.initials: T
authors.lastname: Aoki
authors.forename: M
authors.initials: M
authors.lastname: Seiki
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology* / Q000502:physiology; D002522:Chlorocebus aethiops; D003094:Collagen; D019281:Dimerization; D004338:Drug Combinations; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D005354:Fibrosarcoma; D005780:Gelatin / Q000378:metabolism; D018093:Gelatinases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007797:Laminin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000302:isolation & purification / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004338:Drug Combinations; D004792:Enzyme Precursors; D007797:Laminin; D011506:Proteins; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C059485:matrigel; D019716:Tissue Inhibitor of Metalloproteinase-2; D005780:Gelatin; D003094:Collagen; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; C069860:progelatinase