Reiterer2013 - pseudophosphatase STYX role in ERK signalling

  public model
Model Identifier
BIOMD0000000557
Short description
Reiterer2013 - pseudophosphatase STYX role in ERK signalling

This model is described in the article:

Reiterer V, Fey D, Kolch W, Kholodenko BN, Farhan H.
Proc. Natl. Acad. Sci. U.S.A. 2013 Jul; 110(31): E2934-43

Abstract:

Serine/threonine/tyrosine-interacting protein (STYX) is a catalytically inactive member of the dual-specificity phosphatases (DUSPs) family. Whereas the role of DUSPs in cellular signaling is well explored, the function of STYX is still unknown. Here, we identify STYX as a spatial regulator of ERK signaling. We used predictive-model simulation to test several hypotheses for possible modes of STYX action. We show that STYX localizes to the nucleus, competes with nuclear DUSP4 for binding to ERK, and acts as a nuclear anchor that regulates ERK nuclear export. Depletion of STYX increases ERK activity in both cytosol and nucleus. Importantly, depletion of STYX causes an ERK-dependent fragmentation of the Golgi apparatus and inhibits Golgi polarization and directional cell migration. Finally, we show that overexpression of STYX reduces ERK1/2 activation, thereby blocking PC12 cell differentiation. Overall, our results identify STYX as an important regulator of ERK1/2 signaling critical for cell migration and PC12 cell differentiation.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • Pseudophosphatase STYX modulates cell-fate decisions and cell migration by spatiotemporal regulation of ERK1/2.
  • Reiterer V, Fey D, Kolch W, Kholodenko BN, Farhan H
  • Proceedings of the National Academy of Sciences of the United States of America , 7/ 2013 , Volume 110 , pages: E2934-43 , PubMed ID: 23847209
  • Biotechnology Institute Thurgau, University of Konstanz, Kreuzlingen, Switzerland.
  • Serine/threonine/tyrosine-interacting protein (STYX) is a catalytically inactive member of the dual-specificity phosphatases (DUSPs) family. Whereas the role of DUSPs in cellular signaling is well explored, the function of STYX is still unknown. Here, we identify STYX as a spatial regulator of ERK signaling. We used predictive-model simulation to test several hypotheses for possible modes of STYX action. We show that STYX localizes to the nucleus, competes with nuclear DUSP4 for binding to ERK, and acts as a nuclear anchor that regulates ERK nuclear export. Depletion of STYX increases ERK activity in both cytosol and nucleus. Importantly, depletion of STYX causes an ERK-dependent fragmentation of the Golgi apparatus and inhibits Golgi polarization and directional cell migration. Finally, we show that overexpression of STYX reduces ERK1/2 activation, thereby blocking PC12 cell differentiation. Overall, our results identify STYX as an important regulator of ERK1/2 signaling critical for cell migration and PC12 cell differentiation.
Contributors
Dirk Fey

Metadata information

is
BioModels Database MODEL1410300001
BioModels Database BIOMD0000000557
isDescribedBy
PubMed 23847209
hasTaxon
Taxonomy Homo sapiens
isVersionOf
occursIn
Brenda Tissue Ontology HeLa cell

Curation status
Curated

Original model(s)
ERK-STYX model

Tags
Name Description Size Actions

Model files

BIOMD0000000557_url.xml SBML L2V4 representation of Reiterer2013 - pseudophosphatase STYX role in ERK signalling 63.02 KB Preview | Download

Additional files

BIOMD0000000557-biopax3.owl Auto-generated BioPAX (Level 3) 60.83 KB Preview | Download
BIOMD0000000557_urn.xml Auto-generated SBML file with URNs 62.17 KB Preview | Download
BIOMD0000000557.svg Auto-generated Reaction graph (SVG) 75.38 KB Preview | Download
BIOMD0000000557.vcml Auto-generated VCML file 897.00 bytes Preview | Download
BIOMD0000000557.m Auto-generated Octave file 13.81 KB Preview | Download
BIOMD0000000557.sci Auto-generated Scilab file 576.00 bytes Preview | Download
BIOMD0000000557.png Auto-generated Reaction graph (PNG) 502.57 KB Preview | Download
BIOMD0000000557.xpp Auto-generated XPP file 10.95 KB Preview | Download
BIOMD0000000557-biopax2.owl Auto-generated BioPAX (Level 2) 37.04 KB Preview | Download
BIOMD0000000557.pdf Auto-generated PDF file 276.38 KB Preview | Download

  • Model originally submitted by : Dirk Fey
  • Submitted: 30-Oct-2014 15:05:16
  • Last Modified: 12-Dec-2014 15:08:29
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 12-Dec-2014 15:08:29
    • Submitted by: Dirk Fey
    • With comment: Current version of Reiterer2013 - pseudophosphatase STYX role in ERK signalling
  • Version: 1 public model Download this version
    • Submitted on: 30-Oct-2014 15:05:16
    • Submitted by: Dirk Fey
    • With comment: Original import of modelB_1
Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
(pERKc) => (pERK_ppMEKc)

([Mitogen-activated protein kinase 3]) => ([Mitogen-activated protein kinase 3; Dual specificity mitogen-activated protein kinase kinase 1])
k1_ERKc*pERKc*((ppMEKc_tot*cytosol-pERK_ppMEKc*cytosol)-ERK_ppMEKc)*cytosol-k2_ERKc*pERK_ppMEKc*cytosol

k1_ERKc*[Mitogen-activated protein kinase 3]*(([Dual specificity mitogen-activated protein kinase kinase 1]*cytosol-[Mitogen-activated protein kinase 3; Dual specificity mitogen-activated protein kinase kinase 1]*cytosol)-[Mitogen-activated protein kinase 3; Dual specificity mitogen-activated protein kinase kinase 1])*cytosol-k2_ERKc*[Mitogen-activated protein kinase 3; Dual specificity mitogen-activated protein kinase kinase 1]*cytosol
k2_ERKc = 350.0; k1_ERKc = 1.0
(ppERKc) => (ppERKn)

([Mitogen-activated protein kinase 3]) => ([Mitogen-activated protein kinase 3])
k_ppERKin*ppERKc*cytosol-k_ppERKout*ppERKn*nucleus

k_ppERKin*[Mitogen-activated protein kinase 3]*cytosol-k_ppERKout*[Mitogen-activated protein kinase 3]*nucleus
k_ppERKout = 0.78; k_ppERKin = 0.66
(ppERK_DUSPn) => (pERKn + DUSPn)

([Mitogen-activated protein kinase 3; Dual specificity protein phosphatase 4]) => ([Mitogen-activated protein kinase 3] + [Dual specificity protein phosphatase 4])
kd3_ppERKn*ppERK_DUSPn*nucleus

kd3_ppERKn*[Mitogen-activated protein kinase 3; Dual specificity protein phosphatase 4]*nucleus
kd3_ppERKn = 38.88
(pERK_ppMEKc) => (ppERKc)

([Mitogen-activated protein kinase 3; Dual specificity mitogen-activated protein kinase kinase 1]) => ([Mitogen-activated protein kinase 3])
k3_ERKc*pERK_ppMEKc*cytosol

k3_ERKc*[Mitogen-activated protein kinase 3; Dual specificity mitogen-activated protein kinase kinase 1]*cytosol
k3_ERKc = 13.2
(pERKc + DUSPc) => (pERK_DUSPc)

([Mitogen-activated protein kinase 3] + [Dual specificity protein phosphatase 4]) => ([Mitogen-activated protein kinase 3; Dual specificity protein phosphatase 4])
(kd1_pERKc*pERKc*DUSPc/0.94*cytosol-kd2_pERKc*pERK_DUSPc)*cytosol

(kd1_pERKc*[Mitogen-activated protein kinase 3]*[Dual specificity protein phosphatase 4]/0.94*cytosol-kd2_pERKc*[Mitogen-activated protein kinase 3; Dual specificity protein phosphatase 4])*cytosol
kd2_pERKc = 160.0; kd1_pERKc = 1.0
(ppERKn + STYXn) => (ppERK_STYXn)

([Mitogen-activated protein kinase 3] + [Serine/threonine/tyrosine-interacting protein]) => ([Mitogen-activated protein kinase 3; Serine/threonine/tyrosine-interacting protein])
(k1_ppES*ppERKn*STYXn/0.22*nucleus-k2_ppES*ppERK_STYXn)*nucleus

(k1_ppES*[Mitogen-activated protein kinase 3]*[Serine/threonine/tyrosine-interacting protein]/0.22*nucleus-k2_ppES*[Mitogen-activated protein kinase 3; Serine/threonine/tyrosine-interacting protein])*nucleus
k1_ppES = 1.0; k2_ppES = 60.0
Curator's comment:
(added: 25 Nov 2014, 16:19:05, updated: 25 Nov 2014, 16:19:05)
The figure that is generated here is not the exact reproduction of figure 4 of the reference publication, but the outcome is the same. The total nuclear ERK i.e. the sum of ERKn, pERKn and ppERKn is plotted against time, with varying values of STYX (from 0 to 5000). In the model, STYX=5000 denotes control and STYX=500 denotes knockout. The model was simulated using Copasi v4.14 (Build 89). The plot was generated using Gnuplot.