Tissue Inhibitor of Metalloproteases 3 (TIMP-3): In Vivo Analysis Underpins Its Role as a Master Regulator of Ectodomain Shedding

Abstract

The proteolytical cleavage of transmembrane proteins with subsequent release of their extracellular domain, so-called ectodomain shedding, is a post-translational modification that plays an essential role in several biological processes, such as cell communication, adhesion and migration. Metalloproteases are major proteases in ectodomain shedding, especially the disintegrin metalloproteases (ADAMs) and the membrane-type matrix metalloproteases (MT-MMPs), which are considered to be canonical sheddases for their membrane-anchored topology and for the large number of proteins that they can release. The unique ability of TIMP-3 to inhibit different families of metalloproteases, including the canonical sheddases (ADAMs and MT-MMPs), renders it a master regulator of ectodomain shedding. This review provides an overview of the different functions of TIMP-3 in health and disease, with a major focus on the functional consequences in vivo related to its ability to control ectodomain shedding. Furthermore, herein we describe a collection of mass spectrometry-based approaches that have been used in recent years to identify new functions of sheddases and TIMP-3. These methods may be used in the future to elucidate the pathological mechanisms triggered by the Sorsby’s fundus dystrophy variants of TIMP-3 or to identify proteins released by less well characterized TIMP-3 target sheddases whose substrate repertoire is still limited, thus providing novel insights into the physiological and pathological functions of the inhibitor.

The Repertoire of Tissue Inhibitors of Metalloproteases: Evolution, Regulation of Extracellular Matrix Proteolysis, Engineering and Therapeutic Challenges

“…TIMPs are a group of endogenous inhibitors of metalloproteases whose major function is modulating the turnover of ECM components. TIMPs are expressed in all metazoans, and evidence suggests their role in modulating ancestral ECMs, in the cnidarian mesoglea and in the regulation of ectodomain shedding [ 73 ]. Although metazoan TIMPs show a conserved wedge-like shape across evolutionarily distant species, some structural features are unique for specific TIMPs.…”

Deglycosylation Increases the Aggregation and Angiogenic Properties of Mutant Tissue Inhibitor of Metalloproteinase 3 Protein: Implications for Sorsby Fundus Dystrophy

“…Sorsby Fundus Dystrophy (SFD) is an autosomal dominant, fully penetrant, macular dystrophy with early onset of symptoms, usually in the third or fourth decade of life [1][2][3][4] and is caused by specific mutations in the Tissue Inhibitor of Metalloproteinase-3 (TIMP3) gene [5][6][7][8][9][10][11][12][13][14][15][16][17][18]. The majority of SFD mutations in TIMP3, result in the substitution of a cysteine residue for another amino acid in the C-terminus of the protein.…”