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ADAM17 can be rapidly activated by many stimuli through its transmembrane domain (TMD), with the seven membrane\u2010spanning inactive Rhomboids (iRhom) 1 and 2 implicated as candidate regulatory partners. However, several alternative models of ADAM17 regulation exist that do not involve the iRhoms, such as regulation through disulfide bond exchange or through interaction with charged phospholipids. Here, we report that a non\u2010activatable mutant of ADAM17 with the TMD of betacellulin (BTC) can be rescued by restoring residues from the ADAM17 TMD, but only in\n                    <jats:italic>\n                      Adam17\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    cells, which contain iRhoms, not in\n                    <jats:italic>\n                      iRhom1\/2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    cells. We also provide the first evidence that the extracellular juxtamembrane domains (JMDs) of ADAM17 and iRhom2 regulate the stimulation and substrate selectivity of ADAM17. Interestingly, a point mutation in the ADAM17 JMD identified in a patient with Tetralogy of Fallot, a serious heart valve defect, affects the substrate selectivity of ADAM17 toward Heparin\u2010binding epidermal growth factor like growth factor (HB\u2010EGF), a crucial regulator of heart valve development in mice. These findings provide new insights into the regulation of ADAM17 through an essential interaction with the TMD1 and JMD1 of iRhom2.\n                  <\/jats:p>","DOI":"10.1096\/fj.201902649r","type":"journal-article","created":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T02:04:50Z","timestamp":1582769090000},"page":"4956-4969","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Substrate\u2010selective protein ectodomain shedding by ADAM17 and iRhom2 depends on their juxtamembrane and transmembrane domains"],"prefix":"10.1096","volume":"34","author":[{"given":"Beiyu","family":"Tang","sequence":"first","affiliation":[{"name":"Arthritis and Tissue Degeneration Program Hospital for Special Surgery New York NY USA"},{"name":"Department of Pharmacology Weill Cornell Medicine New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[{"name":"Arthritis and Tissue Degeneration Program Hospital for Special Surgery New York NY USA"},{"name":"Department of Biochemistry, Cellular and Molecular Biology Weill Cornell Medicine New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Maretzky","sequence":"additional","affiliation":[{"name":"Inflammation Program and Department of Internal Medicine Roy J. and Lucille A. Carver College of Medicine University of Iowa Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Manuel","family":"Perez\u2010Aguilar","sequence":"additional","affiliation":[{"name":"Department of Physiology, Biophysics and Systems Biology Weill Cornell Medicine New York NY USA"},{"name":"School of Chemical Sciences Meritorious Autonomous University of Puebla (BUAP) Puebla Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"McIlwain","sequence":"additional","affiliation":[{"name":"Baxter Laboratory in Stem Cell Biology Department of Microbiology and Immunology Stanford University Stanford CA USA"},{"name":"Campbell Family Institute for Breast Cancer Research Princess Margaret Cancer Center University Health Network Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifang","family":"Xie","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital Institute of Reproduction and Development State Key Laboratory of Genetic, Engineering at School of Life Sciences Fudan University Shanghai China"},{"name":"Key Laboratory of Reproduction Regulation of NPFPC Collaborative Innovation Center of Genetics and Development Fudan University Shanghai China"},{"name":"Institutes of Biomedical Sciences Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital Institute of Reproduction and Development State Key Laboratory of Genetic, Engineering at School of Life Sciences Fudan University Shanghai China"},{"name":"Key Laboratory of Reproduction Regulation of NPFPC Collaborative Innovation Center of Genetics and Development Fudan University Shanghai China"},{"name":"Institutes of Biomedical Sciences Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tak 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