Shin2016 - Unveiling Hidden Dynamics of Hippo Signalling

  public model
Model Identifier
BIOMD0000000832
Short description 
This is a mathematical model describing Hippo signalling pathway activity. It includes descriptions of crosstalk with the Akt and ERK MAPK pathways; crosstalk activity is described using complex regulatory mechanisms comprised of competitive protein-protein interactions and phosphorylation mediated feedback loops.
Format
SBML (L2V4)
Related Publication
  • Unveiling Hidden Dynamics of Hippo Signalling: A Systems Analysis.
  • Shin SY, Nguyen LK
  • Genes , 1/ 2016 , Volume 7 , Issue 8 , PubMed ID: 27527217
  • Biomedicine Discovery Institute, Monash University, Clayton Victoria 3800, Australia. sungyoung.shin@monash.edu.
  • The Hippo signalling pathway has recently emerged as an important regulator of cell apoptosis and proliferation with significant implications in human diseases. In mammals, the pathway contains the core kinases MST1/2, which phosphorylate and activate LATS1/2 kinases. The pro-apoptotic function of the MST/LATS signalling axis was previously linked to the Akt and ERK MAPK pathways, demonstrating that the Hippo pathway does not act alone but crosstalks with other signalling pathways to coordinate network dynamics and cellular outcomes. These crosstalks were characterised by a multitude of complex regulatory mechanisms involving competitive protein-protein interactions and phosphorylation mediated feedback loops. However, how these different mechanisms interplay in different cellular contexts to drive the context-specific network dynamics of Hippo-ERK signalling remains elusive. Using mathematical modelling and computational analysis, we uncovered that the Hippo-ERK network can generate highly diverse dynamical profiles that can be clustered into distinct dose-response patterns. For each pattern, we offered mechanistic explanation that defines when and how the observed phenomenon can arise. We demonstrated that Akt displays opposing, dose-dependent functions towards ERK, which are mediated by the balance between the Raf-1/MST2 protein interaction module and the LATS1 mediated feedback regulation. Moreover, Ras displays a multi-functional role and drives biphasic responses of both MST2 and ERK activities; which are critically governed by the competitive protein interaction between MST2 and Raf-1. Our study represents the first in-depth and systematic analysis of the Hippo-ERK network dynamics and provides a concrete foundation for future studies.
Contributors
Submitter of the first revision: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer

Metadata information

is (2 statements)
BioModels Database MODEL1909250001
BioModels Database BIOMD0000000832

isDescribedBy (1 statement)
PubMed 27527217

hasTaxon (1 statement)
Taxonomy Homo sapiens

hasProperty (4 statements)
Mathematical Modelling Ontology Ordinary differential equation model
NCIt NCIT:C38981
Gene Ontology hippo signaling
NCIt NCIT:C38834

Curation status
Curated
Modelling approach(es)
ordinary differential equation model
Tags

Connected external resources

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Name Description Size Actions

Model files
Shin2016.xml SBML L2V4 Representation of Shin2016 - Unveiling Hidden Dynamics of Hippo Signalling 136.09 KB Preview | Download

Additional files
Shin2016.cps COPASI file of Shin2016 - Unveiling Hidden Dynamics of Hippo Signalling 185.68 KB Preview | Download
Shin2016.sedml SED-ML file of Shin2016 - Unveiling Hidden Dynamics of Hippo Signalling 2.93 KB Preview | Download

  • Model originally submitted by : Johannes Meyer
  • Submitted: Sep 25, 2019 10:20:59 AM
  • Last Modified: Oct 10, 2019 11:37:43 AM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Oct 10, 2019 11:37:43 AM
    • Submitted by: Johannes Meyer
    • With comment: Automatically added model identifier BIOMD0000000832
  • Version: 1 public model Download this version
    • Submitted on: Sep 25, 2019 10:20:59 AM
    • Submitted by: Johannes Meyer
    • With comment: Import of Shin2016 - Unveiling Hidden Dynamics of Hippo Signalling

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
MST2uRASSF1A

Ras Association Domain-Containing Protein 1 ; STE20-Like Serine/Threonine-Protein Kinase 		0.23 item
aRaf1

RAF proto-oncogene serine/threonine-protein kinase 		0.0 item
MST2

STE20-Like Serine/Threonine-Protein Kinase 		0.2 item
aMST2

STE20-Like Serine/Threonine-Protein Kinase 		185.6 item
iRaf1

RAF proto-oncogene serine/threonine-protein kinase 		750.0 item
pAkt

AKT kinase 		0.0 item
RASSF1A

Ras Association Domain-Containing Protein 1 		1.77 item
Reactions
Reactions Rate Parameters
MST2 + RASSF1A => MST2uRASSF1A compartment*(ka_22*MST2*RASSF1A-kd_21*MST2uRASSF1A) ka_22 = 0.0684; kd_21 = 0.113
aRaf1 => ipRaf1; ppERK compartment*kc_112*aRaf1*ppERK/(Km_112+aRaf1) kc_112 = 0.002742; Km_112 = 207.1
aMST2 => MST2 compartment*V_21*aMST2/(Km_21+aMST2) Km_21 = 427.3; V_21 = 1414.0
iMST2 + iRaf1 => iRaf1uiMST2 compartment*(ka_71*iMST2*iRaf1-kd_71*iRaf1uiMST2) ka_71 = 28.12; kd_71 = 4.886E-4
Akt => pAkt compartment*kc_11*aEGFR*Akt/(Km_11+Akt) aEGFR = 500.0; Km_11 = 51.21; kc_11 = 0.001149
dMST2 => aMST2 compartment*kd_31*dMST2 kd_31 = 0.6117
aMST2 + RASSF1A => aMST2uRASSF1A compartment*(ka_41*aMST2*RASSF1A-kd_41*aMST2uRASSF1A) ka_41 = 0.4237; kd_41 = 1.226
MST2uRASSF1A => aMST2uRASSF1A compartment*V_51*MST2uRASSF1A/(Km_51+MST2uRASSF1A) Km_51 = 6.708; V_51 = 5.688E-4
Curator's comment:
(added: 10 Oct 2019, 11:37:09, updated: 10 Oct 2019, 11:37:09)
Reproduced plots of Figure 2 from the original publication. Model simulated and plots produced using COPASI 4.24 (Build 197).