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ACVR1\n                    <jats:sup>R206H<\/jats:sup>\n                    is a frequent mutation in both diseases. Pathogenic signaling via the SMAD1\/5 pathway is mediated by Activin A, but how the mutation triggers aberrant signaling is not known. We show that ACVR1 is essential for Activin A\u2010mediated SMAD1\/5 phosphorylation and is activated by two distinct mechanisms. Wild\u2010type ACVR1 is activated by the Activin type I receptors, ACVR1B\/C. In contrast, ACVR1\n                    <jats:sup>R206H<\/jats:sup>\n                    activation does not require upstream kinases, but is predominantly activated via Activin A\u2010dependent receptor clustering, which induces its auto\u2010activation. We use optogenetics and live\u2010imaging approaches to demonstrate Activin A\u2010induced receptor clustering and show it requires the type II receptors ACVR2A\/B. Our data provide molecular mechanistic insight into the pathogenesis of FOP and DIPG by linking the causal activating genetic mutation to disrupted signaling.\n                  <\/jats:p>","DOI":"10.15252\/embj.2020106317","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T11:30:58Z","timestamp":1621337458000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Pathogenic ACVR1R206H activation by Activin A\u2010induced receptor clustering and autophosphorylation"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0123-6539","authenticated-orcid":false,"given":"Anassuya","family":"Ramachandran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8249-5526","authenticated-orcid":false,"given":"Merima","family":"Mehi\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laabiah","family":"Wasim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0784-5703","authenticated-orcid":false,"given":"Dessislava","family":"Malinova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1913-8520","authenticated-orcid":false,"given":"Ilaria","family":"Gori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata K","family":"Blaszczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana M","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2609-6971","authenticated-orcid":false,"given":"Eileen M","family":"Shore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8118-2296","authenticated-orcid":false,"given":"Chris","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8683-4070","authenticated-orcid":false,"given":"Marko","family":"Hyv\u00f6nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4693-7299","authenticated-orcid":false,"given":"Pavel","family":"Tolar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8632-0480","authenticated-orcid":false,"given":"Caroline S","family":"Hill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,18]]},"reference":[{"key":"BFEMBJ2020106317_CR1","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.bone.2017.06.011","volume":"109","author":"DM Alessi Wolken","year":"2018","unstructured":"Alessi Wolken DM, Idone V, Hatsell SJ, Yu PB, Economides AN (2018) The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva. 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