{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T15:57:08Z","timestamp":1791129428703,"version":"4.1.0"},"reference-count":49,"publisher":"Life Science Alliance, LLC","issue":"5","license":[{"start":{"date-parts":[[2019,8,27]],"date-time":"2019-08-27T00:00:00Z","timestamp":1566864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["125440785\u2014SFB877"],"award-info":[{"award-number":["125440785\u2014SFB877"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["RTG1743"],"award-info":[{"award-number":["RTG1743"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["life-science-alliance.org"],"crossmark-restriction":true},"short-container-title":["Life Sci. Alliance"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:p>ADAM17, prominent member of the \u201cDisintegrin and Metalloproteinase\u201d (ADAM) family, controls vital cellular functions through cleavage of transmembrane substrates. Several of these play central roles in oncogenesis and inflammation, yet despite its importance, the mechanism by which ADAM17 is activated is not fully understood. We recently presented evidence that surface exposure of phosphatidylserine (PS) is the penultimate event required for sheddase activation, which occurs upon binding of a membrane-proximal, cationic binding motif to the anionic phospholipid headgroup. Here, we show that mutagenesis of the 3 amino acids constituting the PS-binding motif leads to embryonic lethality in mice. Heterozygotes showed no abnormalities. Primary hepatocytes and fibroblasts were analysed and found to express the mutant protease on the cell surface. However, PMA-stimulated release of ADAM17 substrates was completely abolished. The results directly support the novel concept of transiently externalised PS as essential trigger of extracellular protease function in vivo.<\/jats:p>","DOI":"10.26508\/lsa.201900430","type":"journal-article","created":{"date-parts":[[2019,8,27]],"date-time":"2019-08-27T18:25:10Z","timestamp":1566930310000},"page":"e201900430","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Mutagenesis of the ADAM17-phosphatidylserine\u2013binding motif leads to embryonic lethality in mice"],"prefix":"10.26508","volume":"2","author":[{"given":"Martin","family":"Veit","sequence":"first","affiliation":[{"name":"Department of Dermatology, University of Kiel, Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Ahrens","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Kiel, Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Seidel","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Kiel, Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anselm","family":"Sommer","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Kiel, Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sucharit","family":"Bhakdi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Kiel, Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5140-2235","authenticated-orcid":true,"given":"Karina","family":"Reiss","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Kiel, Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"12380","published-online":{"date-parts":[[2019,8,27]]},"reference":[{"key":"2019082711250462000_2.5.e201900430.1","doi-asserted-by":"publisher","DOI":"10.1038\/385729a0"},{"key":"2019082711250462000_2.5.e201900430.2","doi-asserted-by":"publisher","DOI":"10.1038\/385733a0"},{"key":"2019082711250462000_2.5.e201900430.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5392.1281"},{"key":"2019082711250462000_2.5.e201900430.4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.19.14608"},{"key":"2019082711250462000_2.5.e201900430.5","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0307193"},{"key":"2019082711250462000_2.5.e201900430.6","doi-asserted-by":"publisher","DOI":"10.2174\/138161209788682398"},{"key":"2019082711250462000_2.5.e201900430.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2017.07.001"},{"key":"2019082711250462000_2.5.e201900430.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112050200"},{"key":"2019082711250462000_2.5.e201900430.9","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200307137"},{"key":"2019082711250462000_2.5.e201900430.10","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1548"},{"key":"2019082711250462000_2.5.e201900430.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1100721"},{"key":"2019082711250462000_2.5.e201900430.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2015.02.010"},{"key":"2019082711250462000_2.5.e201900430.13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.5.2686"},{"key":"2019082711250462000_2.5.e201900430.14","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-0775"},{"key":"2019082711250462000_2.5.e201900430.15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802491"},{"key":"2019082711250462000_2.5.e201900430.16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20092366"},{"key":"2019082711250462000_2.5.e201900430.17","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11523"},{"key":"2019082711250462000_2.5.e201900430.18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013433"},{"key":"2019082711250462000_2.5.e201900430.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2017.06.006"},{"key":"2019082711250462000_2.5.e201900430.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2018.08.011"},{"key":"2019082711250462000_2.5.e201900430.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2006.07.002"},{"key":"2019082711250462000_2.5.e201900430.22","doi-asserted-by":"publisher","DOI":"10.1042\/bj3470131"},{"key":"2019082711250462000_2.5.e201900430.23","doi-asserted-by":"publisher","DOI":"10.1126\/science.1214448"},{"key":"2019082711250462000_2.5.e201900430.24","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.196436"},{"key":"2019082711250462000_2.5.e201900430.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.01.034"},{"key":"2019082711250462000_2.5.e201900430.26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.7.3922"},{"key":"2019082711250462000_2.5.e201900430.27","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2121-12-20"},{"key":"2019082711250462000_2.5.e201900430.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2016.11.003"},{"key":"2019082711250462000_2.5.e201900430.29","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.069997"},{"key":"2019082711250462000_2.5.e201900430.30","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2005548"},{"key":"2019082711250462000_2.5.e201900430.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.1214400"},{"key":"2019082711250462000_2.5.e201900430.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2019.06.017"},{"key":"2019082711250462000_2.5.e201900430.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1505649112"},{"key":"2019082711250462000_2.5.e201900430.34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.7.4214"},{"key":"2019082711250462000_2.5.e201900430.35","doi-asserted-by":"crossref","first-page":"229","DOI":"10.59566\/IJBS.2014.10229","article-title":"Reduction of serum ADAM17 level accompanied with decreased cytokines after abatacept therapy in patients with rheumatoid arthritis","volume":"10","author":"Umemura","year":"2014","journal-title":"Int J Biomed Sci"},{"key":"2019082711250462000_2.5.e201900430.36","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03184-4"},{"key":"2019082711250462000_2.5.e201900430.37","first-page":"929","article-title":"Serum levels of ADAM10, ADAM12, ADAM17 AND ADAM28 in colorectal cancer patients","volume":"31","author":"Walkiewicz","year":"2017","journal-title":"J Biol Regul Homeost Agents"},{"key":"2019082711250462000_2.5.e201900430.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2016.09.002"},{"key":"2019082711250462000_2.5.e201900430.39","doi-asserted-by":"publisher","DOI":"10.7554\/elife.17536"},{"key":"2019082711250462000_2.5.e201900430.40","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00469"},{"key":"2019082711250462000_2.5.e201900430.41","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.1242\/jcs.114.20.3631","article-title":"Transient expression of phosphatidylserine at cell-cell contact areas is required for myotube formation","volume":"114","author":"van den Eijnde","year":"2001","journal-title":"J Cell Sci"},{"key":"2019082711250462000_2.5.e201900430.42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.9.3184"},{"key":"2019082711250462000_2.5.e201900430.43","first-page":"3062","article-title":"Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes","volume":"51","author":"Utsugi","year":"1991","journal-title":"Cancer Res"},{"key":"2019082711250462000_2.5.e201900430.44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1987.tb48664.x"},{"key":"2019082711250462000_2.5.e201900430.45","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(87)90282-3"},{"key":"2019082711250462000_2.5.e201900430.46","doi-asserted-by":"publisher","DOI":"10.1080\/19490992.2014.995516"},{"key":"2019082711250462000_2.5.e201900430.47","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-11-012328"},{"key":"2019082711250462000_2.5.e201900430.48","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00020.2015"},{"key":"2019082711250462000_2.5.e201900430.49","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1279"}],"container-title":["Life Science Alliance"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.26508\/lsa.201900430","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T14:05:41Z","timestamp":1704895541000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.life-science-alliance.org\/lookup\/doi\/10.26508\/lsa.201900430"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,27]]},"references-count":49,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,8,27]]},"published-print":{"date-parts":[[2019,10]]}},"alternative-id":["10.26508\/lsa.201900430"],"URL":"https:\/\/doi.org\/10.26508\/lsa.201900430","relation":{},"ISSN":["2575-1077"],"issn-type":[{"value":"2575-1077","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,27]]}}}