title: Domain specific overexpression of TIMP-2 and TIMP-3 reveals MMP-independent functions of TIMPs during Xenopus laevis development.
abstract: Extracellular matrix remodelling mediates many processes including cell migration and differentiation and is regulated through the enzymatic action of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). TIMPs are secreted proteins, consisting of structurally and functionally distinct N- and C-terminal domains. TIMP N-terminal domains inhibit MMP activity, whereas their C-terminal domains may have cell signalling activity. The in vivo role of TIMP N- and C-terminal domains in regulating developmental events has not previously been demonstrated. Here we investigated the roles of TIMP-2 and TIMP-3 N- and C-terminal domains in Xenopus laevis embryos. We show that overexpression of TIMP-2 N- and C-terminal domains results in severe developmental defects and death, as well as unique changes in MMP-2 and -9 expression, indicating that the individual domains may regulate MMPs through distinct mechanisms. In contrast, we show that only the N-terminal, but not the C-terminal domain of TIMP-3, results in developmental defects.
authors.affiliation: Department of Biology, University of Western Ontario, 1151 Richmond Street, London, ON N6A 5B7, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: Nieuwesteeg
authors.forename: L A
authors.initials: LA
authors.lastname: Walsh
authors.forename: M A
authors.initials: MA
authors.lastname: Fox
authors.forename: S
authors.initials: S
authors.lastname: Damjanovski
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2