Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation

Anassuya Ramachandran, Merima Mehić, Laabiah Wasim, Dessislava Malinova, Ilaria Gori, Beata K Blaszczyk, Diana M Carvalho, Eileen M Shore, Chris Jones, Marko Hyvönen, Pavel Tolar, Caroline S Hill

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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.

Original languageEnglish
Article numbere106317
Number of pages22
JournalThe EMBO Journal
Early online date18 May 2021
DOIs
Publication statusEarly online date - 18 May 2021

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© 2021 The Authors. Published under the terms of the CC BY 4.0 license.

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