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    The Diverse Roles of TIMP-3

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    Submitted by: Jennifer Dewing


    Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment, where it mediates diverse processes including matrix regulation/turnover, inflammation and angiogenesis. Rare TIMP-3 risk alleles and mutations are directly linked with retinopathies such as age-related macular degeneration (AMD) and Sorsby fundus dystrophy, and potentially, through indirect mechanisms, with Alzheimer’s disease. Insights into TIMP-3 activities may be gleaned from studying Sorsby-linked mutations. However, recent findings do not fully support the prevailing hypothesis that a gain of function through the dimerisation of mutated TIMP-3 is responsible for retinopathy. Findings from Alzheimer’s patients suggest a hitherto poorly studied relationship between TIMP-3 and the Alzheimer’s-linked amyloid-beta (A) proteins that warrant further scrutiny. This may also have implications for understanding AMD as aged/diseased retinae contain high levels of A. Findings from TIMP-3 knockout and mutant knock-in mice have not led to new treatments, particularly as the latter does not satisfactorily recapitulate the Sorsby phenotype. However, recent advances in stem cell and in vitro approaches offer novel insights into understanding TIMP-3 pathology in the retina-brain axis, which has so far not been collectively examined. We propose that TIMP-3 activities could extend beyond its hitherto supposed functions to cause age-related changes and disease in these organs.

    1. Introduction

    Tissue inhibitors of metalloproteinases (TIMPs) are proteins expressed ubiquitously in the body which play important roles through their ability to reversibly inhibit enzymes belonging to the zinc protease superfamily, predominantly matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) [1]. The TIMP family consists of four members: TIMP-1, -2, -3 and -4. Whilst TIMPs are widely regarded as broad-range MMP inhibitors, each protein exhibits differences in their specificity. TIMP-3, the focus of this review, is found in chromosome 22q12.3 and is nested within an intron of the gene synapsin 3 (SYN3); a feature shared with TIMP-1 and TIMP-4 which are located within introns of synapsin 1 (SYN1) and synapsin 2 (SYN2), respectively [1]. TIMP-2 however, is not associated with any of the synapsin genes. The relationship between synapsin and TIMPs appears to be evolutionarily conserved, having been identified in the fruit fly (Drosophila melanogaster) and the tiger blowfish (Fugu rubripes) [2], although its nature is yet to be elucidated. There is also considerable conservation in the amino acid structure of TIMP family members. Each protein contains an N-terminal domain of approximately 125 amino acids and a C-terminal domain of 64 amino acids, with each domain stabilised by three disulphide bonds that form between conserved cysteine residues [1][3]. TIMP-3 is considered to have a predominantly extracellular role, as the protein is capable of binding to the extracellular matrix (ECM) via its N or C- terminal domains [4][5]. By contrast, TIMP-1, -2 and -4 proteins were considered to predominantly exist in soluble form within the interstitial space of the ECM. However, it has since been shown that these proteins can also interact with cell surface proteins including CD63 and β-1 integrin [6][7][8]. The interaction of TIMP-3 with ECM proteoglycans is primarily mediated via its C-terminal domain. However, binding to the glycosaminoglycan heparin appears to be mediated via the N-terminus [9]. Of the four members of the TIMP family, TIMP-3 possesses the broadest range of inhibition, targeting all members of the MMP family and several of the ADAM and ADAMTs (a disintegrin and metalloproteases with thrombospondin motifs) family members. Independent of its inhibitory capabilities, TIMP-3 is also involved in promoting cell proliferation and regulating angiogenesis and apoptosis [1].

    The entry is from 10.3390/cells9010039


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