title: Targeting a single function of the multifunctional matrix metalloprotease MT1-MMP: impact on lymphangiogenesis.
abstract: The group of matrix metalloproteases (MMPs) is responsible for multiple processes of extracellular matrix remodeling in the healthy body but also for matrix and tissue destruction during cancer invasion and metastasis. The understanding of the contributions from each individual MMP, both in healthy and pathological events, has been complicated by the lack of specific inhibitors and the fact that some of the potent MMPs are multifunctional enzymes. These factors have also hampered the setup of therapeutic strategies targeting MMP activity. A tempting target is the membrane-associated MT1-MMP, which has well-documented importance in matrix degradation but which takes part in more than one pathway in this regard. In this report, we describe the selective targeting of a single function of this enzyme by means of a specific monoclonal antibody against MT1-MMP, raised in an MT1-MMP knock-out mouse. The antibody blocks the enzyme ability to activate proMMP-2 without interfering with the collagenolytic function or the general proteolytic activity of MT1-MMP. Using this antibody, we have shown that the MT1-MMP-catalyzed activation of proMMP-2 is involved in the outgrowth of cultured lymphatic endothelial cells in a collagen matrix in vitro, as well as in lymphatic vessel sprouting assayed ex vivo. This is the first example of the complete inactivation of a single function of a multifunctional MMP and the use of this strategy to pursue its role.
authors: Finsen Laboratory, Rigshospitalet/BRIC, DK-2200 Copenhagen N, Denmark.
authors: Signe
authors: S
authors: Ingvarsen
authors: Astrid
authors: A
authors: Porse
authors: Charlotte
authors: C
authors: Erpicum
authors: Ludovic
authors: L
authors: Maertens
authors: Henrik J
authors: HJ
authors: Jürgensen
authors: Daniel H
authors: DH
authors: Madsen
authors: Maria C
authors: MC
authors: Melander
authors: Henrik
authors: H
authors: Gårdsvoll
authors: Gunilla
authors: G
authors: Høyer-Hansen
authors: Agnès
authors: A
authors: Noel
authors: Kenn
authors: K
authors: Holmbeck
authors: Lars H
authors: LH
authors: Engelholm
authors: Niels
authors: N
authors: Behrendt
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D004789:Enzyme Activation / Q000235:genetics; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D004792:Enzyme Precursors; C507096:Mmp14 protein, mouse; D009363:Neoplasm Proteins; D018093:Gelatinases; C069860:progelatinase; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14