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Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions

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Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions

This model is described in the article:

Veronica Musante, Lu Li, Jean Kanyo, Tukiet T Lam, Christopher M Colangelo, Shuk Kei Cheng, Harrison Brody, Paul Greengard, Nicolas Le Nov�?�¨re, Angus C Nairn
eLIFE

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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Format
SBML (L3V1)
Related Publication
  • Reciprocal regulation of ARPP-16 by PKA and MAST-3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition
  • Veronica Musante, Lu Li, Jean Kanyo, Tukiet T Lam, Christopher M Colangelo, Shuk Kei Cheng, Harrison Brody, Paul Greengard, Nicolas Le NovÃ??Ã?¨re, Angus C Nairn
  • eLIFE , 9/ 2017
  • Yale University School of Medicine, United States; Babraham Institute, United Kingdom; Yale University School Medicine, United States; The Rockefeller University, United States
  • 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.
Contributors
Lu Li

Metadata information

Curation status
Curated
  • Model originally submitted by : Lu Li
  • Submitted: Jul 2, 2017 1:20:12 PM
  • Last Modified: Oct 6, 2017 10:58:17 AM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Oct 6, 2017 10:58:17 AM
    • Submitted by: Lu Li
    • With comment: Model curated and republished
  • Version: 2 public model Download this version
    • Submitted on: Jul 26, 2017 2:22:12 PM
    • Submitted by: Lu Li
    • With comment: Current version of Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions
  • Version: 1 public model Download this version
    • Submitted on: Jul 2, 2017 1:20:12 PM
    • Submitted by: Lu Li
    • With comment: Original import of Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions
Curator's comment:
(added: 04 Sep 2017, 15:16:08, updated: 04 Sep 2017, 15:16:08)
We use COPASI 4.19 (Build 140) to reproduce Figure3b (the blue line) from the paper.