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Pathogenic ACVR1 R206H activation by Activin A‐induced receptor clustering and autophosphorylation
Author(s) -
Ramachandran Anassuya,
Mehić Merima,
Wasim Laabiah,
Malinova Dessislava,
Gori Ilaria,
Blaszczyk Beata K,
Carvalho Diana M,
Shore Eileen M,
Jones Chris,
Hyvönen Marko,
Tolar Pavel,
Hill Caroline S
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106317
Subject(s) - activin receptor , autophosphorylation , phosphorylation , fibrodysplasia ossificans progressiva , receptor , mutation , signal transduction , biology , cancer research , microbiology and biotechnology , genetics , gene , protein kinase a , anatomy , ossification
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. ACVR1 R206H 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, ACVR1 R206H 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.