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Self-Organization of Polarized Cell Signaling via Autocrine Circuits: Computational Model Analysis

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<!--  FILE :  maly_model_2004_raw.xml

CREATED :  26th February 2004

LAST MODIFIED : 26th February 2004

AUTHOR :  Catherine Lloyd
          The Bioengineering Institute
          The University of Auckland
          
MODEL STATUS :  This model conforms to the CellML 1.0 Specification released on
                10th August 2001, and the 16/01/2002 CellML Metadata 1.0
                Specification.

DESCRIPTION :  This file contains a CellML description of Maly et al's 2004 computational model analysis of self-organisation of polarised cell signalling via autocrine circuits.

CHANGES:  
  
-->
<model xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:pathway_editor="http://www.physiome.com/pathway_editor/1.0#" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:rdf="http://www.w3.org/1999/0P/PP-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns="http://www.cellml.org/cellml/1.0#" pathway_editor:rendering_config_file="maly_model_2004_CellMLrender.xml" cmeta:id="maly_wiley_lauffenburger_2004_version01" name="maly_wiley_lauffenburger_2004_version01">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
  <articleinfo>
  <title>A Computational Model Analysis of the Self-Organisation of Polarised Cell Signalling via Autocrine Circuits</title>
  <author>
    <firstname>Catherine</firstname>
          <surname>Lloyd</surname>
    <affiliation>
      <shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
    </affiliation>
  </author>
</articleinfo>
  <section id="sec_status">
    <title>Model Status</title>
    <para>
            This is the original unchecked version of the model imported from the previous
            CellML model repository, 24-Jan-2006.
          </para>
  </section>
  <sect1 id="sec_structure">
<title>Model Structure</title>

<para>
Autocrine cells both produce signalling modelcules and respond to them.  AN example of an autocrine system is signalling through epidermal growth factor (EGF) receptor (EGFR).  A cell releases EGFR ligands into its environment, and a fraction of the released ligand is recaptured by the receptors at the cell surface.  The activated receptors then trigger a signal transduction cascade, whose effects range from cell proliferation to cell migration behaviour.  An additional effect can be the further production of EGFR ligands, producing a positive feedback loop which results in a sustained activity of the autocrine signalling circuit.  If, as hypothesised, this sustained autoendocrine circuit is localised within a defined domain of the cell, then it may contribute to the intrinsic cell polarity or assymmetry.  
</para>

<para>
The difficulty associated with the experimental investigation of autoendocrine signalling makes computational modelling especially valuable when trying to deduce nature of the molecular mechanisms underlying signalling circuits.  In the Maly <emphasis>et al.</emphasis> 2004 publication described here, the authors develop and analyse a dymanic computational model of autocrine EGFR signalling.  Their description is based on integrating select elements from the models of  <ulink url="${HTML_EXMPL_KHOLODENKO_MODEL}">Kholodenko <emphasis>et al.</emphasis>, Quantification of EGF Receptor Signalling, 1999</ulink>, and of <ulink url="${HTML_EXMPL_MAPK_CASCADE}">Huang and Ferrell, MAPK Cascade, 1996</ulink>, into the existing model of EGFR aurocrine signalling bt Shvartsman <emphasis>et al.</emphasis>, 2002. 
</para>

<para>
It should be noted that although the original Maly <emphasis>et al.</emphasis> model is a spatially distributed dynamic computational model, the spatial parameters in this CellML description have been removed, as CellML is currently unable to handle spatial parameters.  The model is still dynamic.      
</para>

<para>
The complete original paper reference is cited below:
</para>

<para>
<ulink url="http://www.biophysj.org/cgi/content/abstract/86/1/10">Self-Organization of Polarized Cell Signaling via Autocrine Circuits: Computational Model Analysis</ulink>, Ivan V. Maly, H. Steven Wiley, and Douglas A. Lauffenburger, 2004, <ulink url="http://www.biophysj.org/">
            <emphasis>Biophysical Journal</emphasis>
          </ulink>, 86, 10-22.  (<ulink url="http://www.biophysj.org/cgi/content/full/86/1/10">Full text (HTML)</ulink> and <ulink url="http://www.biophysj.org/cgi/reprint/86/1/10.pdf">PDF</ulink> versions of the article are available on the <emphasis>Biophysical Journal</emphasis> website.)  <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=14695245&amp;dopt=Abstract">PubMed ID: 14695245</ulink>
</para>

<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
  <imageobject>
    <objectinfo>
      <title>reaction diagram</title>
    </objectinfo>
    <imagedata fileref="../images/maly_model_2004/maly_2004.png" />
  </imageobject>
</mediaobject>
<caption>Components of the autocrine EGFR signalling system and their interactions in the model.  Transport, covalent modifications, and protein binding processes are shown by solid arrows.  Catalysation is shown by a dashed arrow.  EGFR is a receptor of ligand L; Gbr2 is an adaptor protein; Sos is an activator protein, Raf, MEK and ERK are protein kinases; p denotes the phosphorylated form of a protein and pp is a double-phosphorylated form.</caption>
</informalfigure>

<para>
Model siumulations supported the hypothesis that autocrine EGFR siganlling circuits could contribute to the generation and/or maintainance of intrinsic cell spatial polarity, possibly realted to migration as ell as tissue organisation.
</para>

</sect1>
</article>
</documentation>
  
  

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    <rdf:RDF>
      <rdf:Description rdf:about="L">
        <dc:title>L</dc:title>
        <dcterms:alternative>extracellular concentration of EGFR ligand</dcterms:alternative>  
      </rdf:Description>
    </rdf:RDF> 
    <variable units="molar" public_interface="out" name="L" initial_value="1.0E-9" />
    
    <variable units="m2_per_s" name="DL" initial_value="1.0E-12" />
    
    <variable units="second" public_interface="in" name="time" />
    
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          <ci> L </ci>
        </apply>
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        <dcterms:alternative>surface density of EGFR</dcterms:alternative>  
      </rdf:Description>
    </rdf:RDF> 
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    <variable units="second_order_rate_constant" public_interface="in" name="kon" />
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    <variable units="second" public_interface="in" name="time" />
    
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        <eq /> 
        <apply>
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          <bvar>
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          <ci>R</ci> 
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        <apply>
          <minus />
          <apply>
            <times />
            <ci> koff </ci>
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    <rdf:RDF>
      <rdf:Description rdf:about="C">
        <dc:title>C</dc:title>
        <dcterms:alternative>surface density of ligand-receptor complexes</dcterms:alternative>  
      </rdf:Description>
    </rdf:RDF> 
    <variable units="per_m2" public_interface="out" name="C" initial_value="2.0E16" />
    
    <variable units="second_order_rate_constant" public_interface="in" name="kon" />
    <variable units="first_order_rate_constant" public_interface="in" name="koff" />
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    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
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            <apply>
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            <plus />
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              <times />
              <ci> koff </ci>
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            <apply>
              <times />
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              <ci> Grb </ci>
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        <dcterms:alternative>surface density of extracellular ligand-receptor-Grb2 complex</dcterms:alternative>  
      </rdf:Description>
    </rdf:RDF> 
    <variable units="molar" public_interface="out" name="CGrb" initial_value="0.0" />
    
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        <dcterms:alternative>surface density of extracellular ligand-receptor-Grb2-Sos complex</dcterms:alternative>  
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      </rdf:Description>
    </rdf:RDF> 
    <variable units="molar" public_interface="out" name="Sos" initial_value="5.0E-8" />
    
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    <variable units="molar" public_interface="in" name="pSos" />
    <variable units="molar" public_interface="in" name="ppERK" />
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            <apply>
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            <apply>
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            <apply>
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              <ci> Sos </ci>
              <ci> Grb </ci>
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            <apply>
              <times />
              <ci> kps </ci>
              <ci> ppERK </ci>
              <ci> Sos </ci>
            </apply>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>
  
  <component cmeta:id="GrbSos" name="GrbSos">
    <rdf:RDF>
      <rdf:Description rdf:about="GrbSos">
        <dc:title>GrbSos</dc:title>
        <dcterms:alternative>Grb2-Sos complex concentration</dcterms:alternative>  
      </rdf:Description>
    </rdf:RDF> 
    <variable units="molar" public_interface="out" name="GrbSos" initial_value="0.0" />
    
    <variable units="second_order_rate_constant" public_interface="in" name="kasg" />
    <variable units="first_order_rate_constant" public_interface="in" name="kdsg" />
    <variable units="m2_per_s" public_interface="in" name="D" />
    <variable units="molar" public_interface="in" name="Grb" />
    <variable units="molar" public_interface="in" name="Sos" />
    <variable units="second" public_interface="in" name="time" />
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq /> 
        <apply>
          <partialdiff /> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>GrbSos</ci> 
        </apply>
        <apply>
          <minus />
          <apply>
            <plus />
            <apply>
              <times />
              <ci> D </ci>
              <ci> GrbSos </ci>
            </apply>
            <apply>
              <times />
              <ci> kasg </ci>
              <ci> Grb </ci>
              <ci> Sos </ci>
            </apply>
          </apply>
          <apply>
            <times />
            <ci> kdsg </ci>
            <ci> GrbSos </ci>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>
  
  <component cmeta:id="pSos" name="pSos">
    <rdf:RDF>
      <rdf:Description rdf:about="pSos">
        <dc:title>pSos</dc:title>
        <dcterms:alternative>phophorylated Sos concentration</dcterms:alternative>  
      </rdf:Description>
    </rdf:RDF> 
    <variable units="molar" public_interface="out" name="pSos" initial_value="0.0" />
    
    <variable units="second_order_rate_constant" public_interface="in" name="kps" />
    <variable units="first_order_rate_constant" public_interface="in" name="kdps" />
    <variable units="m2_per_s" public_interface="in" name="D" />
    <variable units="molar" public_interface="in" name="ppERK" />
    <variable units="molar" public_interface="in" name="Sos" />
    <variable units="second" public_interface="in" name="time" />
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq /> 
        <apply>
          <partialdiff /> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>pSos</ci> 
        </apply>
        <apply>
          <minus />
          <apply>
            <plus />
            <apply>
              <times />
              <ci> D </ci>
              <ci> pSos </ci>
            </apply>
            <apply>
              <times />
              <ci>Â