Reciprocal regulation of ARPP-16 by PKA and MAST-3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition
- Yale University School of Medicine, United States
- Babraham Institute, United Kingdom
- Yale University School Medicine, United States
- The Rockefeller University, United States
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.
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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.
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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Reciprocal regulation of ARPP-16 by PKA and MAST-3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition
eLife 6:e24998.
https://doi.org/10.7554/eLife.24998
