Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop

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.

Data availability

We are providing source files for the data shown in the main figures of the manuscript.

Article and author information

Author details

  1. Senem Aykul

    Skeletal Diseases TFA, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Senem Aykul, 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)..
  2. Richard A Corpina

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    No competing interests declared.
  3. Erich J Goebel

    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States
    Competing interests
    No competing interests declared.
  4. Camille J Cunanan

    Skeletal Diseases TFA, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    No competing interests declared.
  5. Alexandra Dimitriou

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    No competing interests declared.
  6. Hyonjong Kim

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Hyonjong Kim, 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)..
  7. Qian Zhang

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Qian Zhang, 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)..
  8. Ashique Rafique

    Therapeutic Antibodies, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Ashique Rafique, 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)..
  9. Raymond Leidich

    Bioassay, Molecular Biology, and Protein Development, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Raymond Leidich, 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)..
  10. Xin Wang

    Bioassay, Molecular Biology, and Protein Development, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Xin Wang, 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)..
  11. Joyce McClain

    Genome Engineering Technologies, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Joyce McClain, 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)..
  12. Johanna Jimenez

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Johanna Jimenez, 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)..
  13. Kalyan C Nannuru

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Kalyan C Nannuru, 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)..
  14. Nyanza J Rothman

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Nyanza J Rothman, 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)..
  15. John B Lees-Shepard

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    John B Lees-Shepard, 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)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1275-5799
  16. Erik Martinez-Hackert

    Michigan State University, East Lansing, United States
    Competing interests
    No competing interests declared.
  17. Andrew J Murphy

    Research & Development, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Andrew J Murphy, 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)..
  18. Thomas B Thompson

    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States
    Competing interests
    No competing interests declared.
  19. Aris N Economides

    Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, United States
    For correspondence
    aris.economides@regeneron.com
    Competing interests
    Aris N Economides, 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)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6508-8942
  20. Vincent Idone

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    For correspondence
    vincent.idone@regeneron.com
    Competing interests
    Vincent Idone, 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)..

Funding

The authors declare that there was no funding for this work.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols.

Reviewing Editor

  1. Karen Lyons

Publication history

  1. Received: December 19, 2019
  2. Accepted: June 8, 2020
  3. Accepted Manuscript published: June 9, 2020 (version 1)
  4. Version of Record published: June 30, 2020 (version 2)
  5. Version of Record updated: July 15, 2020 (version 3)

Copyright

© 2020, Aykul et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Senem Aykul
  2. Richard A Corpina
  3. Erich J Goebel
  4. Camille J Cunanan
  5. Alexandra Dimitriou
  6. Hyonjong Kim
  7. Qian Zhang
  8. Ashique Rafique
  9. Raymond Leidich
  10. Xin Wang
  11. Joyce McClain
  12. Johanna Jimenez
  13. Kalyan C Nannuru
  14. Nyanza J Rothman
  15. John B Lees-Shepard
  16. Erik Martinez-Hackert
  17. Andrew J Murphy
  18. Thomas B Thompson
  19. Aris N Economides
  20. Vincent Idone
(2020)
Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop
eLife 9:e54582.
https://doi.org/10.7554/eLife.54582
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