Pathogenic ACVR1R206H activation by Activin A‐induced receptor clustering and autophosphorylation
| العنوان: | Pathogenic ACVR1R206H activation by Activin A‐induced receptor clustering and autophosphorylation |
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| المؤلفون: | Beata K. Blaszczyk, Marko Hyvönen, Eileen M. Shore, Anassuya Ramachandran, Pavel Tolar, Diana Carvalho, Chris Jones, Caroline S. Hill, Dessislava Malinova, Laabiah Wasim, Merima Mehić, Ilaria Gori |
| المساهمون: | Ramachandran, Anassuya [0000-0002-0123-6539], Mehić, Merima [0000-0001-8249-5526], Malinova, Dessislava [0000-0003-0784-5703], Gori, Ilaria [0000-0003-1913-8520], Shore, Eileen M [0000-0003-2609-6971], Jones, Chris [0000-0001-8118-2296], Hyvönen, Marko [0000-0001-8683-4070], Tolar, Pavel [0000-0003-4693-7299], Hill, Caroline S [0000-0002-8632-0480], Apollo - University of Cambridge Repository |
| المصدر: | The EMBO Journal Ramachandran, A, Mehić, M, Wasim, L, Malinova, D, Gori, I, Blaszczyk, B K, Carvalho, D M, Shore, E M, Jones, C, Hyvönen, M, Tolar, P & Hill, C S 2021, ' Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation ', The EMBO Journal . https://doi.org/10.15252/embj.2020106317 |
| بيانات النشر: | John Wiley and Sons Inc., 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | animal structures, Biology, ACVR1, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Animals, Cluster Analysis, Humans, FOP, Phosphorylation, Receptor, Molecular Biology, ACVR1B, ACVR1R206H, 030304 developmental biology, Cancer, 0303 health sciences, General Immunology and Microbiology, General Neuroscience, Autophosphorylation, Articles, Activin A, medicine.disease, Cell biology, Activins, HEK293 Cells, Myositis Ossificans, Fibrodysplasia ossificans progressiva, embryonic structures, Mutation, DIPG, NIH 3T3 Cells, Receptor clustering, Activin Receptors, Type I, 030217 neurology & neurosurgery, receptor clustering, ACVR2A, Signal Transduction |
| الوصف: | 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. Activation of mutated TGF‐β family type I receptors independent of upstream type II receptor kinase activity promotes SMAD signaling in human glioma cells. |
| وصف الملف: | application/pdf; text/xml |
| اللغة: | English |
| تدمد: | 1460-2075 0261-4189 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bbceb285c61a07768cad6ed3521d0f31 http://europepmc.org/articles/PMC8280795 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....bbceb285c61a07768cad6ed3521d0f31 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602075 02614189 |
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