dc.contributor.author | Ramachandran, A | |
dc.contributor.author | Mehić, M | |
dc.contributor.author | Wasim, L | |
dc.contributor.author | Malinova, D | |
dc.contributor.author | Gori, I | |
dc.contributor.author | Blaszczyk, BK | |
dc.contributor.author | Carvalho, DM | |
dc.contributor.author | Shore, EM | |
dc.contributor.author | Jones, C | |
dc.contributor.author | Hyvönen, M | |
dc.contributor.author | Tolar, P | |
dc.contributor.author | Hill, CS | |
dc.date.accessioned | 2021-08-05T10:55:55Z | |
dc.date.available | 2021-08-05T10:55:55Z | |
dc.date.issued | 2021-07-15 | |
dc.identifier.citation | The EMBO journal, 2021, 40 (14), pp. e106317 - ? | |
dc.identifier.issn | 0261-4189 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4725 | |
dc.identifier.eissn | 1460-2075 | |
dc.identifier.doi | 10.15252/embj.2020106317 | |
dc.description.abstract | Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are debilitating diseases that share causal mutations in ACVR1, a TGF-β family type I receptor. ACVR1R206H 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-mediated SMAD1/5 phosphorylation and is activated by two distinct mechanisms. Wild-type ACVR1 is activated by the Activin type I receptors, ACVR1B/C. In contrast, ACVR1R206H activation does not require upstream kinases, but is predominantly activated via Activin A-dependent receptor clustering, which induces its auto-activation. We use optogenetics and live-imaging approaches to demonstrate Activin A-induced 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. | |
dc.format | Print-Electronic | |
dc.format.extent | e106317 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | WILEY | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-03-26 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.15252/embj.2020106317 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The EMBO journal | |
pubs.issue | 14 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.publication-status | Published | |
pubs.volume | 40 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Glioma Team | |
icr.researchteam | Glioma Team | |
dc.contributor.icrauthor | Jones, Chris | |