Musante2017 - Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions and PKA inhibits MAST3

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Model Identifier
BIOMD0000000644
Short description
Musante2017 - Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions and PKA inhibits MAST3

This model is described in the article:

Musante V, Li L, Kanyo J, Lam TT, Colangelo CM, Cheng SK, Brody AH, Greengard P, Le Novère N, Nairn AC.
Elife 2017 Jun; 6:

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.

This model is hosted on BioModels Database and identified by: BIOMD0000000644.

To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8.

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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 Novère, Angus C Nairn
  • eLIFE , 9/ 2017 , DOI: 10.7554/eLife.24998
  • 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, administrator

Metadata information

is
BioModels Database MODEL1707020001
BioModels Database BIOMD0000000644
isDescribedBy
PubMed 28613156
hasTaxon
Taxonomy Mus sp.
isDerivedFrom
Brenda Tissue Ontology HEK-293T cell
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model

Curation status
Curated


Tags
Name Description Size Actions

Model files

BIOMD0000000644_url.xml SBML L3V1 representation of Musante2017 - Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions and PKA inhibits MAST3 55.90 KB Preview | Download

Additional files

BIOMD0000000644.svg Auto-generated Reaction graph (SVG) 845.00 bytes Preview | Download
BIOMD0000000644.png Auto-generated Reaction graph (PNG) 4.27 KB Preview | Download
BIOMD0000000644.sci Auto-generated Scilab file 380.00 bytes Preview | Download
BIOMD0000000644.vcml Auto-generated VCML file 900.00 bytes Preview | Download
BIOMD0000000644.xpp Auto-generated XPP file 5.87 KB Preview | Download
BIOMD0000000644_urn.xml Auto-generated SBML file with URNs 55.69 KB Preview | Download
BIOMD0000000644-biopax2.owl Auto-generated BioPAX (Level 2) 2.95 KB Preview | Download
ARPP-16_Layer1and2_mutualInhibitions_PKAinhibitsMAST3.cps COPASI file that reproduces green line from Figure3-supplementary figure 1 69.01 KB Preview | Download
BIOMD0000000644-biopax3.owl Auto-generated BioPAX (Level 3) 5.54 KB Preview | Download
BIOMD0000000644.m Auto-generated Octave file 8.24 KB Preview | Download
ARPP-16_Layer1and2_mutualInhibitions_PKAinhibitsMAST3.sedml SED-ML file that reproduces green line from Figure3-supplementary figure 1 9.33 KB Preview | Download

  • Model originally submitted by : Lu Li
  • Submitted: Jul 2, 2017 1:22:21 PM
  • Last Modified: Dec 21, 2018 6:24:57 PM
Revisions
  • Version: 4 public model Download this version
    • Submitted on: Dec 21, 2018 6:24:57 PM
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: ARPP-16_Layer1and2_mutualInhibitions_PKAinhibitsMAST3.cps, ARPP-16_Layer1and2_mutualInhibitions_PKAinhibitsMAST3.sedml
  • Version: 3 public model Download this version
    • Submitted on: Oct 6, 2017 11:10:34 AM
    • Submitted by: Lu Li
    • With comment: Model curated and republished
  • Version: 2 public model Download this version
    • Submitted on: Jul 26, 2017 2:27:03 PM
    • Submitted by: Lu Li
    • With comment: Current version of Musante2017 - Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions and PKA inhibits MAST3
  • Version: 1 public model Download this version
    • Submitted on: Jul 2, 2017 1:22:21 PM
    • Submitted by: Lu Li
    • With comment: Original import of Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions plus PKA inhibits MAST3
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
A46

urn:miriam:pr:PR P56212-2
9.80000000000001 ��mol
BB

urn:miriam:pr:PR%3AP56212-2
11.8161515151515 ��mol
A88

urn:miriam:pr:PR P56212-2
0.199999999999989 ��mol
M

Microtubule-associated serine/threonine-protein kinase 3
0.0093807 ��mol
PKA

cAMP-dependent protein kinase catalytic subunit alpha
0.01 ��mol
Complex

protein phosphatase type 2A complex
1.9958693267679 ��mol
Reactions
Reactions Rate Parameters
ModelValue_1 = 2.0
Curator's comment:
(added: 07 Sep 2017, 15:47:53, updated: 07 Sep 2017, 15:47:53)
We use COPASI 4.19 (Build 140) to reproduce Figure3-supplementary figure 1 (the green line).