{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T07:23:20Z","timestamp":1782372200804,"version":"3.54.5"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T00:00:00Z","timestamp":1689552000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100013117","name":"International Fibrodysplasia Ossificans Progressiva Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013117","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Bone &amp; Mineral Res"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic condition characterized by altered skeletal development and extraskeletal bone formation. All cases of FOP are caused by mutations in the type I bone morphogenetic protein (BMP) receptor gene\n                    <jats:italic>ACVR1<\/jats:italic>\n                    that result in overactivation of the BMP signaling pathway. Activation of the wild\u2010type ACVR1 kinase requires assembly of a tetrameric type I and II BMP receptor complex followed by phosphorylation of the ACVR1 GS domain by type II BMP receptors. Previous studies showed that the FOP\u2010mutant ACVR1\u2010R206H required type II BMP receptors and presumptive glycine\/serine\u2010rich (GS) domain phosphorylation for overactive signaling. Structural modeling of the ACVR1\u2010R206H mutant kinase domain supports the idea that FOP mutations alter the conformation of the GS domain, but it is unclear how this leads to overactive signaling. Here we show, using a developing zebrafish embryo BMP signaling assay, that the FOP\u2010mutant receptors ACVR1\u2010R206H and \u2010G328R have reduced requirements for GS domain phosphorylatable sites to signal compared to wild\u2010type ACVR1. Further, ligand\u2010independent and ligand\u2010dependent signaling through the FOP\u2010mutant ACVR1 receptors have distinct GS domain phosphorylatable site requirements. ACVR1\u2010G328R showed increased GS domain serine\/threonine requirements for ligand\u2010independent signaling compared to ACVR1\u2010R206H, whereas it exhibited reduced serine\/threonine requirements for ligand\u2010dependent signaling. Remarkably, while ACVR1\u2010R206H does not require the type I BMP receptor partner, Bmpr1, to signal, a ligand\u2010dependent GS domain mutant of ACVR1\u2010R206H could signal independently of Bmpr1 only when Bmp7 ligand was overexpressed. Of note, unlike human ACVR1\u2010R206H, the zebrafish paralog Acvr1l\u2010R203H does not show increased signaling activity. However, in domain\u2010swapping studies, the human kinase domain, but not the human GS domain, was sufficient to confer overactive signaling to the Acvr1l\u2010R203H receptor. Together these results reflect the importance of GS domain activation and kinase domain functions in regulating ACVR1 signaling and identify mechanisms of reduced regulatory constraints conferred by FOP mutations. \u00a9 2023 American Society for Bone and Mineral Research (ASBMR).\n                  <\/jats:p>","DOI":"10.1002\/jbmr.4869","type":"journal-article","created":{"date-parts":[[2023,6,17]],"date-time":"2023-06-17T11:34:30Z","timestamp":1687001670000},"page":"1364-1385","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Reduced\n                    <scp>GS<\/scp>\n                    Domain Serine\/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I\n                    <scp>BMP<\/scp>\n                    Receptor\n                    <scp>ACVR1<\/scp>\n                    in the Zebrafish"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8306-0620","authenticated-orcid":false,"given":"Robyn S.","family":"Allen","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology University of Pennsylvania, Perelman School of Medicine  Philadelphia PA USA"},{"name":"Department of Orthopaedic Surgery University of Pennsylvania, Perelman School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5568-3035","authenticated-orcid":false,"given":"William D.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology University of Pennsylvania, Perelman School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9583-9436","authenticated-orcid":false,"given":"Maya","family":"Hale","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology University of Pennsylvania, Perelman School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2375-6498","authenticated-orcid":false,"given":"Bailey N.","family":"Warder","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology University of Pennsylvania, Perelman School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2609-6971","authenticated-orcid":false,"given":"Eileen M.","family":"Shore","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery University of Pennsylvania, Perelman School of Medicine  Philadelphia PA USA"},{"name":"Department of Genetics University of Pennsylvania, Perelman School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9979-1564","authenticated-orcid":false,"given":"Mary C.","family":"Mullins","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology University of Pennsylvania, Perelman School of Medicine  Philadelphia PA 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