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Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop.
- Source :
-
ELife [Elife] 2020 Jun 09; Vol. 9. Date of Electronic Publication: 2020 Jun 09. - Publication Year :
- 2020
-
Abstract
- Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild-type ACVR1. To explore the role of the NSC, we generated 'agonist-only' Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins, we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC's physiological role in corresponding knock-in mice.<br />Competing Interests: SA, RC, CC, AD, HK, QZ, AR, RL, XW, JM, JJ, KN, NR, JL, AM, AE, VI The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666). EG, EM, TT No competing interests declared<br /> (© 2020, Aykul et al.)
- Subjects :
- Activin Receptors, Type I genetics
Activins genetics
Animals
Bone Morphogenetic Protein Receptors, Type II genetics
Bone Morphogenetic Protein Receptors, Type II metabolism
Bone Morphogenetic Proteins genetics
Gene Knock-In Techniques
Mice
Mice, Transgenic
Mutation
Myositis Ossificans pathology
Activin Receptors, Type I metabolism
Activins metabolism
Bone Morphogenetic Proteins metabolism
Myositis Ossificans genetics
Signal Transduction genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 9
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 32515349
- Full Text :
- https://doi.org/10.7554/eLife.54582