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.
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Authors | 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 |
Journal | The EMBO journal
(EMBO J)
Vol. 40
Issue 14
Pg. e106317
(07 15 2021)
ISSN: 1460-2075 [Electronic] England |
PMID | 34003511
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2021 The Authors. Published under the terms of the CC BY 4.0 license. |
Chemical References |
- activin A
- Activins
- ACVR1 protein, human
- Activin Receptors, Type I
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Topics |
- Activin Receptors, Type I
(genetics, metabolism)
- Activins
(genetics, metabolism)
- Animals
- Cell Line
- Cluster Analysis
- HEK293 Cells
- Humans
- Mice
- Mutation
(genetics)
- Myositis Ossificans
(genetics)
- NIH 3T3 Cells
- Phosphorylation
(genetics)
- Signal Transduction
(genetics)
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