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

Elife. 2017 Jun 14;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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Gene Expression Regulation*
  • HEK293 Cells
  • Humans
  • Microtubule-Associated Proteins / metabolism*
  • Phosphoproteins / metabolism*
  • Protein Phosphatase 2 / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*

Substances

  • Microtubule-Associated Proteins
  • Phosphoproteins
  • cyclic AMP-regulated phosphoprotein 16
  • Cyclic AMP
  • MAST3 protein, human
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Phosphatase 2