Ramachandran, A; Mehić, M; Wasim, L; Malinova, D; Gori, I; Blaszczyk, BK; Carvalho, DM; ... Hill, CS; + view all Ramachandran, A; Mehić, M; Wasim, L; Malinova, D; Gori, I; Blaszczyk, BK; Carvalho, DM; Shore, EM; Jones, C; Hyvönen, M; Tolar, P; Hill, CS; - view fewer (2021) Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation. The EMBO Journal , Article e106317. 10.15252/embj.2020106317. (In press).

Preview

Text Tolar_Pathogenic ACVR1^{R206H} activation by Activin A-induced receptor clustering and autophosphorylation_VoR.pdf - Published Version Download (4MB) | Preview

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.

Download activity - last month

Export as CSVJSONXML

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as JSONCSVXML

Archive Staff Only

View Item