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Tissue inhibitors of metalloproteinases

DOI: 10.1186/gb-2011-12-11-233

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The naturally occurring inhibitory activities of the matrix metalloproteinases (MMPs) were initially identified in many cell and tissue culture studies, carried out over several decades. Between 1985 and 1996, however, four members of the tissue inhibitor of metalloproteinases (TIMP) family were definitively identified at the gene level in mammals. In fact, orthologs of the TIMPs are widely distributed across the animal kingdom and have now been identified in species as widely separated as Trichoplax, Hydra, molluscs, worms and insects, as well as in vertebrates such as fish and birds. Plants do have metzincins, but no plant TIMP ortholog has been identified.TIMP1 was originally cloned in 1985 when it was found to have an erythroid potentiating activity [1] and to be an inhibitor of metalloproteinases [2]. TIMP2 was cloned in 1990 by Stetler-Stevenson et al. [3], TIMP3 by Pavloff and colleagues in 1992 [4], and TIMP4 in 1996 [5]. These proteins act as significant regulators of the activities of MMPs and, in some instances, of other metalloendopeptidases of the metzincin clan, namely the disintegrin metalloproteinases (ADAM) and the disintegrin metalloproteinases with thrombospondin motifs (ADAMTS). TIMPs inhibit with a 1:1 molar stoichiometry. Their importance in modulating the ability of a cell to control its extracellular environment, from the remodeling of the extracellular matrix to the interaction of cells via adhesion and signaling molecules such as growth factors has long been appreciated [6], but the significance of TIMPs as both proteinase inhibitors and signaling molecules in their own right is only just beginning to be documented [7].The four mammalian TIMPs are thought to be products of gene duplication because there is a single gene in insects, but orthologs of all four proteins are not found in all vertebrates. The TIMP proteins share a similar domain structure, composed of an amino-terminal domain and a carboxy-terminal sub-domain. TIMP1 and TIMP3 see


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