Maeda2006_MyosinPhosphorylation

  public model
Model Identifier
BIOMD0000000088
Short description

The model reproduces Fig 2B, D, F, and 2H. The dynamics correspond to a stimulus of 1 U/ml of thrombin which is equal to 0.01 uM. Phosphorylated MLC is the sum of pMLC (s359) and ppMLC (s360). A slight discrepancy in peak values of species between the figure in the paper and simulation result might be due to different initial conditions in the two sets. The model was successfully tested on MathSBML. It is possible to simulate the model on other software that do not support "Events" at this time by removing the "listOfEvents" and substituting a value of 0.01 for thrombin (s2). This does not change the model very much. With the latter format, the model was also successfully tested on Copasi.


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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Format
SBML (L2V1)
Related Publication
  • Ca2+ -independent phospholipase A2-dependent sustained Rho-kinase activation exhibits all-or-none response.
  • Maeda A, Ozaki Y, Sivakumaran S, Akiyama T, Urakubo H, Usami A, Sato M, Kaibuchi K, Kuroda S
  • Genes to cells : devoted to molecular & cellular mechanisms , 9/ 2006 , Volume 11 , pages: 1071-1083 , PubMed ID: 16923126
  • Undergraduate Program for Bioinformatics and Systems Biology, Graduate School of Information Science and Technology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • Sustained contraction of cells depends on sustained Rho-associated kinase (Rho-kinase) activation. We developed a computational model of the Rho-kinase pathway to understand the systems characteristics. Thrombin-dependent in vivo transient responses of Rho activation and Ca2+ increase could be reproduced in silico. Low and high thrombin stimulation induced transient and sustained phosphorylation, respectively, of myosin light chain (MLC) and myosin phosphatase targeting subunit 1 (MYPT1) in vivo. The transient phosphorylation of MLC and MYPT1 could be reproduced in silico, but their sustained phosphorylation could not. This discrepancy between in vivo and in silico in the sustained responses downstream of Rho-kinase indicates that a missing pathway(s) may be responsible for the sustained Rho-kinase activation. We found, experimentally, that the sustained phosphorylation of MLC and MYPT1 exhibit all-or-none responses. Bromoenol lactone, a specific inhibitor of Ca2+ -independent phospholipase A2 (iPLA2), inhibited sustained phosphorylation of MLC and MYPT1, which indicates that sustained Rho-kinase activation requires iPLA2 activity. Thus, the systems analysis of the Rho-kinase pathway identified a novel iPLA2-dependent mechanism of the sustained Rho-kinase activation, which exhibits an all-or-none response.
Contributors
Yu-ichi Ozaki

Metadata information

is
BioModels Database MODEL7944007619
BioModels Database BIOMD0000000088
Gene Ontology regulation of Rho protein signal transduction
Gene Ontology actin cytoskeleton organization
isDescribedBy
PubMed 16923126
hasTaxon
Taxonomy Homo sapiens
isPartOf
KEGG Pathway Regulation of actin cytoskeleton - Homo sapiens (human)
Curation status
Curated
Tags
Name Description Size Actions

Model files
BIOMD0000000088_url.xml SBML L2V1 representation of Maeda2006_MyosinPhosphorylation 241.65 KB Preview | Download

Additional files
BIOMD0000000088-biopax3.owl Auto-generated BioPAX (Level 3) 329.43 KB Preview | Download
BIOMD0000000088_urn.xml Auto-generated SBML file with URNs 233.62 KB Preview | Download
BIOMD0000000088.sci Auto-generated Scilab file 67.00 bytes Preview | Download
BIOMD0000000088.m Auto-generated Octave file 50.63 KB Preview | Download
BIOMD0000000088.pdf Auto-generated PDF file 721.11 KB Preview | Download
BIOMD0000000088.png Auto-generated Reaction graph (PNG) 1.98 MB Preview | Download
BIOMD0000000088-biopax2.owl Auto-generated BioPAX (Level 2) 200.41 KB Preview | Download
BIOMD0000000088.svg Auto-generated Reaction graph (SVG) 274.02 KB Preview | Download
BIOMD0000000088.xpp Auto-generated XPP file 38.43 KB Preview | Download
BIOMD0000000088.vcml Auto-generated VCML file 322.23 KB Preview | Download

  • Model originally submitted by : Yu-ichi Ozaki
  • Submitted: 28-Jan-2007 23:57:52
  • Last Modified: 08-Apr-2016 16:36:16
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 08-Apr-2016 16:36:16
    • Submitted by: Yu-ichi Ozaki
    • With comment: Current version of Maeda2006_MyosinPhosphorylation
  • Version: 1 public model Download this version
    • Submitted on: 28-Jan-2007 23:57:52
    • Submitted by: Yu-ichi Ozaki
    • With comment: Original import of BIOMD0000000088.xml.origin
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
Rho-kinase

Rho-associated protein kinase 1 		0.042 ÎĽmol
DAG

diglyceride ; Diacylglycerol 		0.0 ÎĽmol
MLC

Myosin light chain phosphate ; Myosin light chain 1/3, skeletal muscle isoform 		0.6 ÎĽmol
MYPT1.Rho-kinase

Rho-associated protein kinase 1 ; Protein phosphatase 1 regulatory subunit 12A 		0.0 ÎĽmol
MYPT1.MLC

Myosin light chain 1/3, skeletal muscle isoform ; Protein phosphatase 1 regulatory subunit 12A 		0.0 ÎĽmol
MLCK.MLC

Myosin light chain kinase 2, skeletal/cardiac muscle ; Myosin light chain 1/3, skeletal muscle isoform 		0.0 ÎĽmol
MLCK.4Ca super 2 plus endsuper .CaM.MLC

calcium(2+) ; Myosin light chain kinase 2, skeletal/cardiac muscle ; Calmodulin-3Calmodulin-1Calmodulin-2 ; Myosin light chain 1/3, skeletal muscle isoform ; Calmodulin ; Calcium cation 		0.0 ÎĽmol
Reactions
Reactions Rate Parameters
(Rho-kinase + MLC) => (Rho-kinase.MLC)

([Rho-associated protein kinase 1] + [Myosin light chain phosphate; Myosin light chain 1/3, skeletal muscle isoform]) => ([Rho-associated protein kinase 1; Myosin light chain 1/3, skeletal muscle isoform])		 c1*((1+ratio)*Vmax*s124*s359/Km-Vmax*ratio*s362)

c1*((1+ratio)*Vmax*[Rho-associated protein kinase 1]*[Myosin light chain phosphate; Myosin light chain 1/3, skeletal muscle isoform]/Km-Vmax*ratio*[Rho-associated protein kinase 1; Myosin light chain 1/3, skeletal muscle isoform])		 Vmax=1.28 per_sec; Km=4.5099 microMolar; ratio=16.617 dimensionless
(Rho-kinase.MLC) => (MLC + Rho-kinase)

([Rho-associated protein kinase 1; Myosin light chain 1/3, skeletal muscle isoform]) => ([Myosin light chain; Myosin light chain 1/3, skeletal muscle isoform] + [Rho-associated protein kinase 1])		 c1*Vmax*s362

c1*Vmax*[Rho-associated protein kinase 1; Myosin light chain 1/3, skeletal muscle isoform]		 Vmax=1.28 per_sec
(MYPT1.Rho-kinase) => (Rho-kinase + MYPT1_PPase)

([Rho-associated protein kinase 1; Protein phosphatase 1 regulatory subunit 12A]) => ([Rho-associated protein kinase 1] + [Protein phosphatase 1 regulatory subunit 12A])		 c1*Vmax*s463

c1*Vmax*[Rho-associated protein kinase 1; Protein phosphatase 1 regulatory subunit 12A]		 Vmax=1.46 per_sec
(DAG) => (PC)

([diglyceride; Diacylglycerol]) => ([PC])		 c1*kf*s153

c1*kf*[diglyceride; Diacylglycerol]		 kf=0.15 per_sec
(PKC.Ca_super_2_plus__endsuper_ + DAG) => (PKC.Ca_super_2_plus__endsuper_.DAG)

([calcium(2+); Protein kinase C alpha type; Calcium cation] + [diglyceride; Diacylglycerol]) => ([diglyceride; calcium(2+); Protein kinase C alpha type; Diacylglycerol; Calcium cation])		 c1*(kf*s566*s153-kb*s565)

c1*(kf*[calcium(2+); Protein kinase C alpha type; Calcium cation]*[diglyceride; Diacylglycerol]-kb*[diglyceride; calcium(2+); Protein kinase C alpha type; Diacylglycerol; Calcium cation])		 kf=0.004 per_uM_per_sec; kb=8.6348 per_sec
(MLC + MLCK.4Ca_super_2_plus__endsuper_.CaM) => (MLCK.4Ca_super_2_plus__endsuper_.CaM.MLC)

([Myosin light chain phosphate; Myosin light chain 1/3, skeletal muscle isoform] + [calcium(2+); Calmodulin-3Calmodulin-1Calmodulin-2; Myosin light chain kinase 2, skeletal/cardiac muscle; Calmodulin; Calcium cation]) => ([calcium(2+); Myosin light chain kinase 2, skeletal/cardiac muscle; Calmodulin-3Calmodulin-1Calmodulin-2; Myosin light chain 1/3, skeletal muscle isoform; Calmodulin; Calcium cation])		 c1*((1+ratio)*Vmax*s295*s359/Km-Vmax*ratio*s506)

c1*((1+ratio)*Vmax*[calcium(2+); Calmodulin-3Calmodulin-1Calmodulin-2; Myosin light chain kinase 2, skeletal/cardiac muscle; Calmodulin; Calcium cation]*[Myosin light chain phosphate; Myosin light chain 1/3, skeletal muscle isoform]/Km-Vmax*ratio*[calcium(2+); Myosin light chain kinase 2, skeletal/cardiac muscle; Calmodulin-3Calmodulin-1Calmodulin-2; Myosin light chain 1/3, skeletal muscle isoform; Calmodulin; Calcium cation])		 Vmax=3.67 per_sec; Km=10.019 microMolar; ratio=1.7299 dimensionless
(MLCK.2Ca_super_2_plus__endsuper_.CaM.MLC) => (MLC + MLCK.2Ca_super_2_plus__endsuper_.CaM)

([calcium(2+); Myosin light chain kinase 2, skeletal/cardiac muscle; Calmodulin-3Calmodulin-1Calmodulin-2; Myosin light chain 1/3, skeletal muscle isoform; Calmodulin; Calcium cation]) => ([Myosin light chain phosphate; Myosin light chain 1/3, skeletal muscle isoform] + [calcium(2+); Calmodulin-3Calmodulin-1Calmodulin-2; Myosin light chain kinase 2, skeletal/cardiac muscle; Calmodulin; Calcium cation])		 c1*Vmax*s539

c1*Vmax*[calcium(2+); Myosin light chain kinase 2, skeletal/cardiac muscle; Calmodulin-3Calmodulin-1Calmodulin-2; Myosin light chain 1/3, skeletal muscle isoform; Calmodulin; Calcium cation]		 Vmax=3.67 per_sec
(MYPT1.MLC) => (MLC + MYPT1_PPase)

([Myosin light chain 1/3, skeletal muscle isoform; Protein phosphatase 1 regulatory subunit 12A]) => ([Myosin light chain phosphate; Myosin light chain 1/3, skeletal muscle isoform] + [Protein phosphatase 1 regulatory subunit 12A])		 c1*Vmax*s480

c1*Vmax*[Myosin light chain 1/3, skeletal muscle isoform; Protein phosphatase 1 regulatory subunit 12A]		 Vmax=9.317 per_sec
(MLC + MYPT1_PPase) => (MYPT1.MLC)

([Myosin light chain phosphate; Myosin light chain 1/3, skeletal muscle isoform] + [Protein phosphatase 1 regulatory subunit 12A]) => ([Myosin light chain 1/3, skeletal muscle isoform; Protein phosphatase 1 regulatory subunit 12A])		 c1*((1+ratio)*Vmax*s351*s359/Km-Vmax*ratio*s480)

c1*((1+ratio)*Vmax*[Protein phosphatase 1 regulatory subunit 12A]*[Myosin light chain phosphate; Myosin light chain 1/3, skeletal muscle isoform]/Km-Vmax*ratio*[Myosin light chain 1/3, skeletal muscle isoform; Protein phosphatase 1 regulatory subunit 12A])		 Vmax=9.317 per_sec; Km=16.0 microMolar; ratio=7.5865 dimensionless
(MLCK.MLC) => (MLC + MLCK)

([Myosin light chain kinase 2, skeletal/cardiac muscle; Myosin light chain 1/3, skeletal muscle isoform]) => ([Myosin light chain; Myosin light chain 1/3, skeletal muscle isoform] + [Myosin light chain kinase 2, skeletal/cardiac muscle])		 c1*Vmax*s491

c1*Vmax*[Myosin light chain kinase 2, skeletal/cardiac muscle; Myosin light chain 1/3, skeletal muscle isoform]		 Vmax=3.67 per_sec
Curator's comment:
(added: 24 Jan 2007, 01:59:09, updated: 24 Jan 2007, 01:59:09)
Plots correspond to Fig 2B, D, F, and 2H of the paper. Results obtained from Cell Designer.