{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T11:02:04Z","timestamp":1771930924343,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kennedy Trust for Rheumatology Research","award":["390857198"],"award-info":[{"award-number":["390857198"]}]},{"name":"Kennedy Trust for Rheumatology Research","award":["2018\u2014PDR\u201400799"],"award-info":[{"award-number":["2018\u2014PDR\u201400799"]}]},{"name":"Deutsche Forschungsgemeinschaft","award":["390857198"],"award-info":[{"award-number":["390857198"]}]},{"name":"Deutsche Forschungsgemeinschaft","award":["2018\u2014PDR\u201400799"],"award-info":[{"award-number":["2018\u2014PDR\u201400799"]}]},{"DOI":"10.13039\/501100007074","name":"Fondazione con il Sud","doi-asserted-by":"publisher","award":["390857198"],"award-info":[{"award-number":["390857198"]}],"id":[{"id":"10.13039\/501100007074","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007074","name":"Fondazione con il Sud","doi-asserted-by":"publisher","award":["2018\u2014PDR\u201400799"],"award-info":[{"award-number":["2018\u2014PDR\u201400799"]}],"id":[{"id":"10.13039\/501100007074","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Membranes"],"abstract":"<jats:p>A disintegrin and metalloproteinase 15 (ADAM15) is a member of the ADAM family of sheddases. Its genetic ablation in mice suggests that ADAM15 plays an important role in a wide variety of biological functions, including cartilage homeostasis. Nevertheless, while the substrate repertoire of other members of the ADAM family, including ADAM10 and ADAM17, is largely established, little is known about the substrates of ADAM15 and how it exerts its biological functions. Herein, we used unbiased proteomics to identify ADAM15 substrates and proteins regulated by the proteinase in chondrocyte-like HTB94 cells. ADAM15 silencing did not induce major changes in the secretome composition of HTB94 cells, as revealed by two different proteomic approaches. Conversely, overexpression of ADAM15 remodeled the secretome, with levels of several secreted proteins being altered compared to GFP-overexpressing controls. However, the analysis did not identify potential substrates of the sheddase, i.e., transmembrane proteins released by ADAM15 in the extracellular milieu. Intriguingly, secretome analysis and immunoblotting demonstrated that ADAM15 overexpression increased secreted levels of tissue inhibitor of metalloproteinases 3 (TIMP-3), a major regulator of extracellular matrix turnover. An inactive form of ADAM15 led to a similar increase in the inhibitor, indicating that ADAM15 regulates TIMP-3 secretion by an unknown mechanism independent of its catalytic activity. In conclusion, high-resolution quantitative proteomics of HTB94 cells manipulated to have increased or decreased ADAM15 expression did not identify canonical substrates of the proteinase in the steady state, but it revealed that ADAM15 can modulate the secretome in a catalytically-independent manner.<\/jats:p>","DOI":"10.3390\/membranes12060578","type":"journal-article","created":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T03:33:18Z","timestamp":1654054398000},"page":"578","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Quantitative Proteomics Reveals That ADAM15 Can Have Proteolytic-Independent Functions in the Steady State"],"prefix":"10.3390","volume":"12","author":[{"given":"Chun-Yao","family":"Yang","sequence":"first","affiliation":[{"name":"Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Bonelli","sequence":"additional","affiliation":[{"name":"Proteomics Group of Fondazione Ri.MED, Research Department IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Via E. Tricomi 5, 90145 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Calligaris","sequence":"additional","affiliation":[{"name":"Proteomics Group of Fondazione Ri.MED, Research Department IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Via E. Tricomi 5, 90145 Palermo, Italy"},{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7389-7555","authenticated-orcid":false,"given":"Anna Paola","family":"Carreca","sequence":"additional","affiliation":[{"name":"Proteomics Group of Fondazione Ri.MED, Research Department IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Via E. Tricomi 5, 90145 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan A.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Strasse 17, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2211-2575","authenticated-orcid":false,"given":"Stefan F.","family":"Lichtenthaler","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Strasse 17, 81377 Munich, Germany"},{"name":"Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Troeberg","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia, Bob Champion Research and Education Building, Rosalind Franklin Road, Norwich NR4 7UQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone D.","family":"Scilabra","sequence":"additional","affiliation":[{"name":"Proteomics Group of Fondazione Ri.MED, Research Department IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Via E. Tricomi 5, 90145 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5614","DOI":"10.1128\/MCB.23.16.5614-5624.2003","article-title":"Potential role for ADAM15 in pathological neovascularization in mice","volume":"23","author":"Horiuchi","year":"2003","journal-title":"Mol. Cell. 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