Rendering of the source text

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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:  
  
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<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 model contains partial differentials and as such can not currently be solved by existing CellML tools.
          </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="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="pMEK">
        <dc:title>pMEK</dc:title>
        <dcterms:alternative>phosphorylated MEK concentration</dcterms:alternative>  
      </rdf:Description>
    </rdf:RDF> 
    <variable units="molar" public_interface="out" name="pMEK" initial_value="0.0"/>
    
    <variable units="molar" name="MEKtot" initial_value="3.0E-7"/>
    <variable units="first_order_rate_constant" name="k3" initial_value="0.75"/>
    <variable units="molar" name="K3" initial_value="1.5E-8"/>
    <variable units="molar" name="K6" initial_value="1.5E-8"/>
    <variable units="flux" name="V6" initial_value="2.25E-8"/>
    
    <variable units="molar" public_interface="in" name="K4"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k4"/>
    <variable units="molar" public_interface="in" name="K5"/>
    <variable units="flux" public_interface="in" name="V5"/>
    <variable units="molar" public_interface="in" name="ppMEK"/>
    <variable units="molar" public_interface="in" name="pRaf"/>
    <variable units="m2_per_s" public_interface="in" name="D"/>
    <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>pMEK</ci> 
        </apply>
        <apply>
          <minus/>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> D </ci>
              <ci> pMEK </ci>
            </apply>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> k3 </ci>
                  <ci> pRaf </ci>
                  <ci> MEKtot </ci>
                </apply>
                <apply>
                  <plus/>
                  <ci> pMEK </ci>
                  <ci> ppMEK </ci>
                </apply>
              </apply>
              <apply>
                <plus/>
                <ci> K3 </ci>
                <apply>
                  <minus/>
                  <ci> MEKtot </ci>
                  <apply>
                    <plus/>
                    <ci> pMEK </ci>
                    <ci> ppMEK </ci>
                  </apply>
                </apply>
              </apply>
            </apply>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> V5 </ci>
                <ci> ppMEK </ci>
              </apply>
              <apply>
                <plus/>
                <ci> K5 </ci>
                <ci> ppMEK </ci>
              </apply>
            </apply>
          </apply>
          <apply>
            <plus/>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> k4 </ci>
                <ci> pRaf </ci>
                <ci> pMEK </ci>
              </apply>
              <apply>
                <plus/>
                <ci> K4 </ci>
                <ci> pMEK </ci>
              </apply>
            </apply>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> V6 </ci>
                <ci> pMEK </ci>
              </apply>
              <apply>
                <plus/>
                <ci> K6 </ci>
                <ci> pMEK </ci>
              </apply>
            </apply>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>
  
  <component cmeta:id="ppMEK" name="ppMEK">
    <rdf:RDF>
      <rdf:Description rdf:about="ppMEK">
        <dc:title>ppMEK</dc:title>
        <dcterms:alternative>bisphosphorylated MEK concentration</dcterms:alternative>  
      </rdf:Description>
    </rdf:RDF> 
    <variable units="molar" public_interface="out" name="ppMEK" initial_value="0.0"/>
    
    <variable units="molar" public_interface="in" name="K4"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k4"/>
    <variable units="molar" public_interface="in" name="K5"/>
    <variable units="flux" public_interface="in" name="V5"/>
    <variable units="molar" public_interface="in" name="pMEK"/>
    <variable units="molar" public_interface="in" name="pRaf"/>
    <variable units="m2_per_s" public_interface="in" name="D"/>
    <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>ppMEK</ci> 
        </apply>
        <apply>
          <minus/>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> D </ci>
              <ci> ppMEK </ci>
            </apply>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> k4 </ci>
                <ci> pRaf </ci>
                <ci> pMEK </ci>
              </apply>
              <apply>
                <plus/>
                <ci> K4 </ci>
                <ci> pMEK </ci>
              </apply>
            </apply>
          </apply>
          <apply>
            <divide/>
            <apply>
              <times/>
              <ci> V5 </ci>
              <ci> ppMEK </ci>
            </apply>
            <apply>
              <plus/>
              <ci> K5 </ci>
              <ci> ppMEK </ci>
            </apply>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>
  
  <component cmeta:id="pERK" name="pERK">
    <rdf:RDF>
      <rdf:Description rdf:about="pERK">
        <dc:title>pERK</dc:title>
        <dcterms:alternative>phosphorylated ERK concentration</dcterms:alternative>  
      </rdf:Description>
    </rdf:RDF> 
    <variable units="molar" public_interface="out" name="pERK" initial_value="0.0"/>
    
    <variable units="molar" name="ERKtot" initial_value="3.0E-7"/>
    <variable units="first_order_rate_constant" name="k7" initial_value="0.75"/>
    <variable units="molar" name="K7" initial_value="1.5E-8"/>
    <variable units="molar" name="K10" initial_value="1.5E-8"/>
    <variable units="flux" name="V10" initial_value="1.0E-8"/>
    
    <variable units="molar" public_interface="in" name="K8"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k8"/>
    <variable units="molar" public_interface="in" name="K9"/>
    <variable units="flux" public_interface="in" name="V9"/>
    <variable units="molar" public_interface="in" name="ppERK"/>
    <variable units="molar" public_interface="in" name="ppMEK"/>
    <variable units="m2_per_s" public_interface="in" name="D"/>
    <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>pERK</ci> 
        </apply>
        <apply>
          <minus/>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> D </ci>
              <ci> pERK </ci>
            </apply>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> k7 </ci>
                  <ci> ppMEK </ci>
                  <ci> ERKtot </ci>
                </apply>
                <apply>
                  <plus/>
                  <ci> pERK </ci>
                  <ci> ppERK </ci>
                </apply>
              </apply>
              <apply>
                <plus/>
                <ci> K7 </ci>
                <apply>
                  <minus/>
                  <ci> ERKtot </ci>
                  <apply>
                    <plus/>
                    <ci> pERK </ci>
                    <ci> ppERK </ci>
                  </apply>
                </apply>
              </apply>
            </apply>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> V9 </ci>
                <ci> ppERK </ci>
              </apply>
              <apply>
                <plus/>
                <ci> K9 </ci>
                <ci> ppERK </ci>
              </apply>
            </apply>
          </apply>
          <apply>
            <plus/>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> k8 </ci>
                <ci> ppMEK </ci>
                <ci> pERK </ci>
              </apply>
              <apply>
                <plus/>
                <ci> K8 </ci>
                <ci> pERK </ci>
              </apply>
            </apply>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> V10 </ci>
                <ci> pERK </ci>
              </apply>
              <apply>
                <plus/>
                <ci> K10 </ci>
                <ci> pERK </ci>
              </apply>
            </apply>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>
  
  <component cmeta:id="ppERK" name="ppERK">
    <rdf:RDF>
      <rdf:Description rdf:about="ppERK">
        <dc:title>ppERK</dc:title>
        <dcterms:alternative>bisphosphorylated ERK concentration</dcterms:alternative>  
      </rdf:Description>
    </rdf:RDF> 
    <variable units="molar" public_interface="out" name="ppERK" initial_value="0.0"/>
    
    <variable units="molar" public_interface="in" name="K8"/>
    <variable units="first_order_rate_constant" public_interface="in" name="k8"/>
    <variable units="molar" public_interface="in" name="K9"/>
    <variable units="flux" public_interface="in" name="V9"/>
    <variable units="molar" public_interface="in" name="pERK"/>
    <variable units="molar" public_interface="in" name="ppMEK"/>
    <variable units="m2_per_s" public_interface="in" name="D"/>
    <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>ppERK</ci> 
        </apply>
        <apply>
          <minus/>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> D </ci>
              <ci> ppERK </ci>
            </apply>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> k8 </ci>
                <ci> ppMEK </ci>
                <ci> pERK </ci>
              </apply>
              <apply>
                <plus/>
                <ci> K8 </ci>
                <ci> pERK </ci>
              </apply>
            </apply>
          </apply>
          <apply>
            <divide/>
            <apply>
              <times/>
              <ci> V9 </ci>
              <ci> ppERK </ci>
            </apply>
            <apply>
              <plus/>
              <ci> K9 </ci>
              <ci> ppERK </ci>
            </apply>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>
  
  <component name="parameters">
    <variable units="second_order_rate_constant" public_interface="out" name="kon" initial_value="1.67E6"/>
    <variable units="first_order_rate_constant" public_interface="out" name="koff" initial_value="1.67E-3"/>
    <variable units="second_order_rate_constant" public_interface="out" name="kasg" initial_value="1.0E5"/>
    <variable units="first_order_rate_constant" public_interface="out" name="kdsg" initial_value="1.5E-3"/>
    <variable units="second_order_rate_constant" public_interface="out" name="kagc" initial_value="3.0E6"/>
    <variable units="first_order_rate_constant" public_interface="out" name="kdgc" initial_value="5.0E-2"/>
    <variable units="second_order_rate_constant" public_interface="out" name="kagsc" initial_value="4.5E6"/>
    <variable units="first_order_rate_constant" public_interface="out" name="kdgsc" initial_value="3.0E-2"/>
    <variable units="second_order_rate_constant" public_interface="out" name="kasc" initial_value="1.0E7"/>
    <variable units="first_order_rate_constant" public_interface="out" name="kdsc" initial_value="6.0E-2"/>
    <variable units="second_order_rate_constant" public_interface="out" name="kps" initial_value="1.0E9"/>
    <variable units="first_order_rate_constant" public_interface="out" name="kdps" initial_value="1.0E-3"/>
    <variable units="m2_per_s" public_interface="out" name="D" initial_value="1.0E-12"/>
    <variable units="molar" public_interface="out" name="K4" initial_value="1.5E-8"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k4" initial_value="0.75"/>
    <variable units="molar" public_interface="out" name="K5" initial_value="1.5E-8"/>
    <variable units="flux" public_interface="out" name="V5" initial_value="2.25E-8"/>
    <variable units="molar" public_interface="out" name="K8" initial_value="1.5E-8"/>
    <variable units="first_order_rate_constant" public_interface="out" name="k8" initial_value="0.75"/>
    <variable units="molar" public_interface="out" name="K9" initial_value="1.5E-8"/>
    <variable units="flux" public_interface="out" name="V9" initial_value="1.0E-8"/>
  </component>
  
  
  <connection>
    <map_components component_2="environment" component_1="L"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="R"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="C"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="CGrb"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="CGrbSos"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="Grb"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="Sos"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="GrbSos"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="pSos"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="pRaf"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection> 
  
  <connection>
    <map_components component_2="environment" component_1="pMEK"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="ppMEK"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="pERK"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="ppERK"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="R"/>
    <map_variables variable_2="kon" variable_1="kon"/>
    <map_variables variable_2="koff" variable_1="koff"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="C"/>
    <map_variables variable_2="kon" variable_1="kon"/>
    <map_variables variable_2="koff" variable_1="koff"/>
    <map_variables variable_2="kagc" variable_1="kagc"/>
    <map_variables variable_2="kdgc" variable_1="kdgc"/>
    <map_variables variable_2="kagsc" variable_1="kagsc"/>
    <map_variables variable_2="kdgsc" variable_1="kdgsc"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="CGrb"/>
    <map_variables variable_2="kagc" variable_1="kagc"/>
    <map_variables variable_2="kdgc" variable_1="kdgc"/>
    <map_variables variable_2="kasc" variable_1="kasc"/>
    <map_variables variable_2="kdsc" variable_1="kdsc"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="CGrbSos"/>
    <map_variables variable_2="kagsc" variable_1="kagsc"/>
    <map_variables variable_2="kdgsc" variable_1="kdgsc"/>
    <map_variables variable_2="kasc" variable_1="kasc"/>
    <map_variables variable_2="kdsc" variable_1="kdsc"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="Grb"/>
    <map_variables variable_2="kasg" variable_1="kasg"/>
    <map_variables variable_2="kdsg" variable_1="kdsg"/>
    <map_variables variable_2="D" variable_1="D"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="Sos"/>
    <map_variables variable_2="kasg" variable_1="kasg"/>
    <map_variables variable_2="kdsg" variable_1="kdsg"/>
    <map_variables variable_2="kps" variable_1="kps"/>
    <map_variables variable_2="kdps" variable_1="kdps"/>
    <map_variables variable_2="D" variable_1="D"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="GrbSos"/>
    <map_variables variable_2="kasg" variable_1="kasg"/>
    <map_variables variable_2="kdsg" variable_1="kdsg"/>
    <map_variables variable_2="D" variable_1="D"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="pSos"/>
    <map_variables variable_2="kps" variable_1="kps"/>
    <map_variables variable_2="kdps" variable_1="kdps"/>
    <map_variables variable_2="D" variable_1="D"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="pRaf"/>
    <map_variables variable_2="D" variable_1="D"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="pMEK"/>
    <map_variables variable_2="k4" variable_1="k4"/>
    <map_variables variable_2="K4" variable_1="K4"/>
    <map_variables variable_2="V5" variable_1="V5"/>
    <map_variables variable_2="K5" variable_1="K5"/>
    <map_variables variable_2="D" variable_1="D"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="ppMEK"/>
    <map_variables variable_2="k4" variable_1="k4"/>
    <map_variables variable_2="K4" variable_1="K4"/>
    <map_variables variable_2="V5" variable_1="V5"/>
    <map_variables variable_2="K5" variable_1="K5"/>
    <map_variables variable_2="D" variable_1="D"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="pERK"/>
    <map_variables variable_2="k8" variable_1="k8"/>
    <map_variables variable_2="K8" variable_1="K8"/>
    <map_variables variable_2="V9" variable_1="V9"/>
    <map_variables variable_2="K9" variable_1="K9"/>
    <map_variables variable_2="D" variable_1="D"/>
  </connection>
  
  <connection>
    <map_components component_2="parameters" component_1="ppERK"/>
    <map_variables variable_2="k8" variable_1="k8"/>
    <map_variables variable_2="K8" variable_1="K8"/>
    <map_variables variable_2="V9" variable_1="V9"/>
    <map_variables variable_2="K9" variable_1="K9"/>
    <map_variables variable_2="D" variable_1="D"/>
  </connection>
  
  <connection>
    <map_components component_2="L" component_1="R"/>
    <map_variables variable_2="L" variable_1="L"/>
  </connection>
  
  <connection>
    <map_components component_2="C" component_1="R"/>
    <map_variables variable_2="C" variable_1="C"/>
    <map_variables variable_2="R" variable_1="R"/>
  </connection>
  
  <connection>
    <map_components component_2="L" component_1="C"/>
    <map_variables variable_2="L" variable_1="L"/>
  </connection>
  
  <connection>
    <map_components component_2="Grb" component_1="C"/>
    <map_variables variable_2="Grb" variable_1="Grb"/>
  </connection>
  
  <connection>
    <map_components component_2="CGrb" component_1="C"/>
    <map_variables variable_2="CGrb" variable_1="CGrb"/>
    <map_variables variable_2="C" variable_1="C"/>
  </connection>
  
  <connection>
    <map_components component_2="CGrbSos" component_1="C"/>
    <map_variables variable_2="CGrbSos" variable_1="CGrbSos"/>
    <map_variables variable_2="C" variable_1="C"/>
  </connection>
  
  <connection>
    <map_components component_2="GrbSos" component_1="C"/>
    <map_variables variable_2="GrbSos" variable_1="GrbSos"/>
  </connection>
  
  <connection>
    <map_components component_2="Grb" component_1="CGrb"/>
    <map_variables variable_2="Grb" variable_1="Grb"/>
  </connection>
  
  <connection>
    <map_components component_2="Sos" component_1="CGrb"/>
    <map_variables variable_2="Sos" variable_1="Sos"/>
  </connection>
  
  <connection>
    <map_components component_2="CGrbSos" component_1="CGrb"/>
    <map_variables variable_2="CGrbSos" variable_1="CGrbSos"/>
    <map_variables variable_2="CGrb" variable_1="CGrb"/>
  </connection>
  
  <connection>
    <map_components component_2="GrbSos" component_1="CGrbSos"/>
    <map_variables variable_2="GrbSos" variable_1="GrbSos"/>
  </connection>
  
  <connection>
    <map_components component_2="Sos" component_1="CGrbSos"/>
    <map_variables variable_2="Sos" variable_1="Sos"/>
  </connection>
  
  <connection>
    <map_components component_2="Sos" component_1="Grb"/>
    <map_variables variable_2="Sos" variable_1="Sos"/>
    <map_variables variable_2="Grb" variable_1="Grb"/>
  </connection>
  
  <connection>
    <map_components component_2="GrbSos" component_1="Grb"/>
    <map_variables variable_2="GrbSos" variable_1="GrbSos"/>
    <map_variables variable_2="Grb" variable_1="Grb"/>
  </connection>
  
  <connection>
    <map_components component_2="GrbSos" component_1="Sos"/>
    <map_variables variable_2="GrbSos" variable_1="GrbSos"/>
    <map_variables variable_2="Sos" variable_1="Sos"/>
  </connection>
  
  <connection>
    <map_components component_2="ppERK" component_1="Sos"/>
    <map_variables variable_2="ppERK" variable_1="ppERK"/>
  </connection>
  
  <connection>
    <map_components component_2="pSos" component_1="Sos"/>
    <map_variables variable_2="pSos" variable_1="pSos"/>
    <map_variables variable_2="Sos" variable_1="Sos"/>
  </connection>
  
  <connection>
    <map_components component_2="ppERK" component_1="pSos"/>
    <map_variables variable_2="ppERK" variable_1="ppERK"/>
  </connection>
  
  <connection>
    <map_components component_2="pRaf" component_1="pMEK"/>
    <map_variables variable_2="pRaf" variable_1="pRaf"/>
  </connection>
  
  <connection>
    <map_components component_2="ppMEK" component_1="pMEK"/>
    <map_variables variable_2="ppMEK" variable_1="ppMEK"/>
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