Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation.
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Embargo End Date
ICR Authors
Authors
Ramachandran, A
Mehić, M
Wasim, L
Malinova, D
Gori, I
Blaszczyk, BK
Carvalho, DM
Shore, EM
Jones, C
Hyvönen, M
Tolar, P
Hill, CS
Mehić, M
Wasim, L
Malinova, D
Gori, I
Blaszczyk, BK
Carvalho, DM
Shore, EM
Jones, C
Hyvönen, M
Tolar, P
Hill, CS
Document Type
Journal Article
Date
2021-07-15
Date Accepted
2021-03-26
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.
Citation
The EMBO journal, 2021, 40 (14), pp. e106317 - ?
Source Title
Publisher
SPRINGERNATURE
ISSN
0261-4189
eISSN
1460-2075
Collections
Research Team
Glioma Team
Glioma Team
Glioma Team