1. Computational and Systems Biology
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Reciprocal regulation of ARPP-16 by PKA and MAST-3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition

  1. Veronica Musante
  2. Lu Li
  3. Jean Kanyo
  4. Tukiet T Lam
  5. Christopher M Colangelo
  6. Shuk Kei Cheng
  7. Harrison Brody
  8. Paul Greengard
  9. Nicolas Le Novère
  10. Angus C Nairn  Is a corresponding author
  1. Yale University School of Medicine, United States
  2. Babraham Institute, United Kingdom
  3. Yale University School Medicine, United States
  4. The Rockefeller University, United States
Research Article
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Cite this article as: eLife 2017;6:e24998 doi: 10.7554/eLife.24998

Abstract

ARPP-16, ARPP-19, and ENSA are inhibitors of protein phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall kinase inhibit PP2A during mitosis. ARPP-16 is expressed in striatal neurons where basal phosphorylation by MAST3 kinase inhibits PP2A and regulates key components of striatal signaling. The ARPP-16/19 proteins were discovered as substrates for PKA, but the function of PKA phosphorylation is unknown. We find that phosphorylation by PKA or MAST3 mutually suppresses the ability of the other kinase to act on ARPP-16. Phosphorylation by PKA also acts to prevent inhibition of PP2A by ARPP-16 phosphorylated by MAST3. Moreover, PKA phosphorylates MAST3 at multiple sites resulting in its inhibition. Mathematical modeling highlights the role of these three regulatory interactions to create a switch-like response to cAMP. Together the results suggest a complex antagonistic interplay between the control of ARPP-16 by MAST3 and PKA that creates a mechanism whereby cAMP mediates PP2A disinhibition.

Article and author information

Author details

  1. Veronica Musante

    Department of Psychiatry, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lu Li

    Babraham Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Jean Kanyo

    W.M. Keck Biotechnology Resource Laboratory, Yale University School Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Tukiet T Lam

    W.M. Keck Biotechnology Resource Laboratory, Yale University School Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christopher M Colangelo

    W.M. Keck Biotechnology Resource Laboratory, Yale University School Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Shuk Kei Cheng

    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Harrison Brody

    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Paul Greengard

    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Nicolas Le Novère

    Babraham Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6309-7327
  10. Angus C Nairn

    Department of Psychiatry, Yale University School of Medicine, New Haven, United States
    For correspondence
    angus.nairn@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7075-0195

Funding

National Institute on Drug Abuse (DA018343)

  • Angus C Nairn

National Institutes of Health (DA10044 NS091336)

  • Veronica Musante
  • Paul Greengard
  • Angus C Nairn

State of Connecticut Department of Mental Health and Addiction Services

  • Angus C Nairn

Brain and Behavior Research Foundation

  • Veronica Musante

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Roger J Davis, University of Massachusetts Medical School, United States

Publication history

  1. Received: January 10, 2017
  2. Accepted: June 13, 2017
  3. Accepted Manuscript published: June 14, 2017 (version 1)
  4. Version of Record published: July 18, 2017 (version 2)

Copyright

© 2017, Musante 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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