Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation
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Anassuya Ramachandran Merima Mehic Laabiah Wasim Dessi Malinova Ilaria Gori Beata K Blaszczyk Diana M Carvalho Eileen M Shore Chris Jones Marko Hyvönen Pavel Tolar Caroline HillAbstract
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.
Journal details
Journal The EMBO Journal
Volume 40
Issue number 14
Pages e106317
Available online
Publication date
Full text links
Publisher website (DOI) 10.15252/embj.2020106317
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Europe PubMed Central 34003511
Pubmed 34003511