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Elife. 2017 Jun 14;6. pii: e24998. doi: 10.7554/eLife.24998.

Reciprocal regulation of ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition.

Author information

1
Department of Psychiatry, Yale University School of Medicine, New Haven, United States.
2
The Babraham Institute, Cambridge, United Kingdom.
3
W.M. Keck Biotechnology Resource Laboratory, Yale University School Medicine, New Haven, United states.
4
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, 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.

KEYWORDS:

computational biology; computational model; hek293 cell line; neurons; neuroscience; phosphatase PP2A; purified proteins; systems biology

PMID:
28613156
PMCID:
PMC5515580
DOI:
10.7554/eLife.24998
[Indexed for MEDLINE]
Free PMC Article

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