{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T12:52:51Z","timestamp":1779108771952,"version":"3.51.4"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,11,20]],"date-time":"2018-11-20T00:00:00Z","timestamp":1542672000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004807","name":"California Department of Fish and Game","doi-asserted-by":"publisher","award":["BU 584\u20105\/1"],"award-info":[{"award-number":["BU 584\u20105\/1"]}],"id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate mechanisms underlying the capability of ADAM15 to transform FasL\u2010mediated death\u2010inducing signals into prosurvival activation of Src and focal adhesion kinase (FAK) in rheumatoid arthritis synovial fibroblasts (RASFs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Caspase 3\/7 activity and apoptosis rate were determined in RASFs and ADAM15\u2010transfected T\/C28a4 cells upon Fas\/CD95 triggering using enzyme assays and annexin V staining. Phosphorylated Src and FAK were analyzed by immunoblotting. Interactions of ADAM15 and CD95 with calmodulin (CaM), Src, or FAK were analyzed by pull\u2010downs using CaM\u2013Sepharose and coimmunoprecipitations with specific antibodies. Protein binding assays were performed using recombinant CaM and ADAM15. Immunofluorescence was performed to investigate subcellular colocalization of ADAM15, Fas\/CD95, and CaM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The antiapoptotic effect of ADAM15 in FasL\u2010stimulated cells was demonstrated either by increased apoptosis of cells transfected with an ADAM15 construct lacking the cytoplasmic domain compared to cells transfected with full\u2010length ADAM15 or by reduced apoptosis resistance of RASFs upon RNA interference silencing of ADAM15. Fas ligation triggered a Ca<jats:sup>2+<\/jats:sup>\u00a0release\u2010activated Ca<jats:sup>2+<\/jats:sup>\/calcium release\u2010activated calcium channel protein 1 (CRAC\/Orai1) channel\u2013dependent CaM recruitment to Fas\/CD95 and ADAM15 in the cell membrane. Simultaneously, Src associated with CaM was shown to become engaged in the ADAM15 complex also containing cytoplasmic\u2010bound FAK. Accordingly, Fas ligation in RASFs led to ADAM15\u2010dependent phosphorylation of Src and FAK, which was associated with increased survival. Pharmacologic interference with either the CaM inhibitor trifluoperazine or the CRAC\/Orai inhibitor BTP\u20102 simultaneously applied with FasL synergistically enhanced Fas\u2010mediated apoptosis in RASFs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>ADAM15 provides a scaffold for formation of CaM\u2010dependent prosurvival signaling complexes upon CRAC\/Orai coactivation by FasL\u2010induced death signals and a potential therapeutic target to break apoptosis resistance in RASFs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40667","type":"journal-article","created":{"date-parts":[[2018,7,13]],"date-time":"2018-07-13T04:16:31Z","timestamp":1531455391000},"page":"63-72","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["ADAM15 in Apoptosis Resistance of Synovial Fibroblasts: Converting Fas\/CD95 Death Signals Into the Activation of Prosurvival Pathways by Calmodulin Recruitment"],"prefix":"10.1002","volume":"71","author":[{"given":"Tomasz","family":"Janczi","sequence":"first","affiliation":[{"name":"University Hospital Frankfurt Goethe University  Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beate B.","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"University Hospital Frankfurt Goethe University  Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuliya","family":"Fehrl","sequence":"additional","affiliation":[{"name":"University Hospital Frankfurt Goethe University  Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pangrazio","family":"DeGiacomo","sequence":"additional","affiliation":[{"name":"University Hospital Frankfurt Goethe University  Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raimund 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