<?xml version="1.0"?>
<!--
This CellML file was generated on 7/05/2009 at 10:55:42 at a.m. using:
COR (0.9.31.1207)
Copyright 2002-2009 Dr Alan Garny
http://COR.physiol.ox.ac.uk/ - COR@physiol.ox.ac.uk
CellML 1.0 was used to generate this model
http://www.CellML.org/
-->
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<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This CellML model runs in both COR and OpenCell to reproduce the graphs in Figure 5 of the Kholodenko et al. 1999 publication.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ABSTRACT: During the past decade, our knowledge of molecular mechanisms involved in growth factor signaling has proliferated almost explosively. However, the kinetics and control of information transfer through signaling networks remain poorly understood. This paper combines experimental kinetic analysis and computational modeling of the short term pattern of cellular responses to epidermal growth factor (EGF) in isolated hepatocytes. The experimental data show transient tyrosine phosphorylation of the EGF receptor (EGFR) and transient or sustained response patterns in multiple signaling proteins targeted by EGFR. Transient responses exhibit pronounced maxima, reached within 15-30 s of EGF stimulation and followed by a decline to relatively low (quasi-steady-state) levels. In contrast to earlier suggestions, we demonstrate that the experimentally observed transients can be accounted for without requiring receptor-mediated activation of specific tyrosine phosphatases, following EGF stimulation. The kinetic model predicts how the cellular response is controlled by the relative levels and activity states of signaling proteins and under what conditions activation patterns are transient or sustained. EGFR signaling patterns appear to be robust with respect to variations in many elemental rate constants within the range of experimentally measured values. On the other hand, we specify which changes in the kinetic scheme, rate constants, and total amounts of molecular factors involved are incompatible with the experimentally observed kinetics of signal transfer. Quantitation of signaling network responses to growth factors allows us to assess how cells process information controlling their growth and differentiation.
</para>
<para>
The original paper reference is cited below:
</para>
<para>
Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor, Boris N. Kholodenko, Oleg V. Demin, Gisela Moehren, and Jan B. Hoek, 1999, <emphasis>The Journal of Biological Chemistry</emphasis>, 274, 30169-30181. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10514507&dopt=Abstract">PubMed ID: 10514507</ulink>
</para>
<informalfigure float="0" id="fig_reaction_diagram">
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<title>reaction diagram</title>
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<imagedata fileref="kholodenko_1999.png"/>
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</mediaobject>
<caption>Kinetic scheme of EGFR signalling mediated by adapter and target proteins.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
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<ci>k3</ci>
<ci>R2</ci>
</apply>
<apply>
<times/>
<ci>k3_</ci>
<ci>RP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v4">
<variable name="v4" public_interface="out" units="flux"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable initial_value="50" name="K4" units="nanomolar"/>
<variable initial_value="450" name="V4" units="flux"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v4</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>V4</ci>
<ci>RP</ci>
</apply>
<apply>
<plus/>
<ci>K4</ci>
<ci>RP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v5">
<variable name="v5" public_interface="out" units="flux"/>
<variable name="R_PL" public_interface="in" units="nanomolar"/>
<variable name="PLC_gamma" public_interface="in" units="nanomolar"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable initial_value="0.06" name="k5" units="second_order_rate_constant"/>
<variable initial_value="0.2" name="k5_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v5</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k5</ci>
<ci>RP</ci>
<ci>PLC_gamma</ci>
</apply>
<apply>
<times/>
<ci>k5_</ci>
<ci>R_PL</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v6">
<variable name="v6" public_interface="out" units="flux"/>
<variable name="R_PL" public_interface="in" units="nanomolar"/>
<variable name="R_PLP" public_interface="in" units="nanomolar"/>
<variable initial_value="1" name="k6" units="first_order_rate_constant"/>
<variable initial_value="0.05" name="k6_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v6</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k6</ci>
<ci>R_PL</ci>
</apply>
<apply>
<times/>
<ci>k6_</ci>
<ci>R_PLP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v7">
<variable name="v7" public_interface="out" units="flux"/>
<variable name="R_PLP" public_interface="in" units="nanomolar"/>
<variable name="PLC_gamma_P" public_interface="in" units="nanomolar"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable initial_value="0.3" name="k7" units="first_order_rate_constant"/>
<variable initial_value="0.006" name="k7_" units="second_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v7</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k7</ci>
<ci>R_PLP</ci>
</apply>
<apply>
<times/>
<ci>k7_</ci>
<ci>RP</ci>
<ci>PLC_gamma_P</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v8">
<variable name="v8" public_interface="out" units="flux"/>
<variable name="PLC_gamma_P" public_interface="in" units="nanomolar"/>
<variable initial_value="100" name="K8" units="nanomolar"/>
<variable initial_value="1" name="V8" units="flux"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v8</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>V8</ci>
<ci>PLC_gamma_P</ci>
</apply>
<apply>
<plus/>
<ci>K8</ci>
<ci>PLC_gamma_P</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v9">
<variable name="v9" public_interface="out" units="flux"/>
<variable name="R_G" public_interface="in" units="nanomolar"/>
<variable name="Grb" public_interface="in" units="nanomolar"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable initial_value="0.003" name="k9" units="second_order_rate_constant"/>
<variable initial_value="0.05" name="k9_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v9</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k9</ci>
<ci>RP</ci>
<ci>Grb</ci>
</apply>
<apply>
<times/>
<ci>k9_</ci>
<ci>R_G</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v10">
<variable name="v10" public_interface="out" units="flux"/>
<variable name="R_G_S" public_interface="in" units="nanomolar"/>
<variable name="SOS" public_interface="in" units="nanomolar"/>
<variable name="R_G" public_interface="in" units="nanomolar"/>
<variable initial_value="0.01" name="k10" units="second_order_rate_constant"/>
<variable initial_value="0.06" name="k10_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v10</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k10</ci>
<ci>R_G</ci>
<ci>SOS</ci>
</apply>
<apply>
<times/>
<ci>k10_</ci>
<ci>R_G_S</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v11">
<variable name="v11" public_interface="out" units="flux"/>
<variable name="R_G_S" public_interface="in" units="nanomolar"/>
<variable name="G_S" public_interface="in" units="nanomolar"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable initial_value="0.03" name="k11" units="first_order_rate_constant"/>
<variable initial_value="4.5e-3" name="k11_" units="second_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v11</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k11</ci>
<ci>R_G_S</ci>
</apply>
<apply>
<times/>
<ci>k11_</ci>
<ci>RP</ci>
<ci>G_S</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v12">
<variable name="v12" public_interface="out" units="flux"/>
<variable name="G_S" public_interface="in" units="nanomolar"/>
<variable name="SOS" public_interface="in" units="nanomolar"/>
<variable name="Grb" public_interface="in" units="nanomolar"/>
<variable initial_value="1.5e-3" name="k12" units="first_order_rate_constant"/>
<variable initial_value="1e-4" name="k12_" units="second_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v12</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k12</ci>
<ci>G_S</ci>
</apply>
<apply>
<times/>
<ci>k12_</ci>
<ci>Grb</ci>
<ci>SOS</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v13">
<variable name="v13" public_interface="out" units="flux"/>
<variable name="R_Sh" public_interface="in" units="nanomolar"/>
<variable name="Shc" public_interface="in" units="nanomolar"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable initial_value="0.09" name="k13" units="second_order_rate_constant"/>
<variable initial_value="0.6" name="k13_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v13</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k13</ci>
<ci>RP</ci>
<ci>Shc</ci>
</apply>
<apply>
<times/>
<ci>k13_</ci>
<ci>R_Sh</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v14">
<variable name="v14" public_interface="out" units="flux"/>
<variable name="R_Sh" public_interface="in" units="nanomolar"/>
<variable name="R_ShP" public_interface="in" units="nanomolar"/>
<variable initial_value="6" name="k14" units="first_order_rate_constant"/>
<variable initial_value="0.06" name="k14_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v14</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k14</ci>
<ci>R_Sh</ci>
</apply>
<apply>
<times/>
<ci>k14_</ci>
<ci>R_ShP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v15">
<variable name="v15" public_interface="out" units="flux"/>
<variable name="R_ShP" public_interface="in" units="nanomolar"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable name="ShP" public_interface="in" units="nanomolar"/>
<variable initial_value="0.3" name="k15" units="first_order_rate_constant"/>
<variable initial_value="9e-4" name="k15_" units="second_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v15</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k15</ci>
<ci>R_ShP</ci>
</apply>
<apply>
<times/>
<ci>k15_</ci>
<ci>ShP</ci>
<ci>RP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v16">
<variable name="v16" public_interface="out" units="flux"/>
<variable name="ShP" public_interface="in" units="nanomolar"/>
<variable initial_value="340" name="K16" units="nanomolar"/>
<variable initial_value="1.7" name="V16" units="flux"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v16</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>V16</ci>
<ci>ShP</ci>
</apply>
<apply>
<plus/>
<ci>K16</ci>
<ci>ShP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v17">
<variable name="v17" public_interface="out" units="flux"/>
<variable name="R_ShP" public_interface="in" units="nanomolar"/>
<variable name="Grb" public_interface="in" units="nanomolar"/>
<variable name="R_Sh_G" public_interface="in" units="nanomolar"/>
<variable initial_value="0.003" name="k17" units="second_order_rate_constant"/>
<variable initial_value="0.1" name="k17_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v17</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k17</ci>
<ci>R_ShP</ci>
<ci>Grb</ci>
</apply>
<apply>
<times/>
<ci>k17_</ci>
<ci>R_Sh_G</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v18">
<variable name="v18" public_interface="out" units="flux"/>
<variable name="R_Sh_G" public_interface="in" units="nanomolar"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable name="Sh_G" public_interface="in" units="nanomolar"/>
<variable initial_value="0.3" name="k18" units="first_order_rate_constant"/>
<variable initial_value="9e-4" name="k18_" units="second_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v18</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k18</ci>
<ci>R_Sh_G</ci>
</apply>
<apply>
<times/>
<ci>k18_</ci>
<ci>RP</ci>
<ci>Sh_G</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v19">
<variable name="v19" public_interface="out" units="flux"/>
<variable name="R_Sh_G_S" public_interface="in" units="nanomolar"/>
<variable name="SOS" public_interface="in" units="nanomolar"/>
<variable name="R_Sh_G" public_interface="in" units="nanomolar"/>
<variable initial_value="0.01" name="k19" units="second_order_rate_constant"/>
<variable initial_value="2.14e-2" name="k19_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v19</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k19</ci>
<ci>R_Sh_G</ci>
<ci>SOS</ci>
</apply>
<apply>
<times/>
<ci>k19_</ci>
<ci>R_Sh_G_S</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v20">
<variable name="v20" public_interface="out" units="flux"/>
<variable name="Sh_G_S" public_interface="in" units="nanomolar"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable name="R_Sh_G_S" public_interface="in" units="nanomolar"/>
<variable initial_value="0.12" name="k20" units="first_order_rate_constant"/>
<variable initial_value="2.4e-4" name="k20_" units="second_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v20</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k20</ci>
<ci>R_Sh_G_S</ci>
</apply>
<apply>
<times/>
<ci>k20_</ci>
<ci>Sh_G_S</ci>
<ci>RP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v21">
<variable name="v21" public_interface="out" units="flux"/>
<variable name="Sh_G" public_interface="in" units="nanomolar"/>
<variable name="Grb" public_interface="in" units="nanomolar"/>
<variable name="ShP" public_interface="in" units="nanomolar"/>
<variable initial_value="0.003" name="k21" units="second_order_rate_constant"/>
<variable initial_value="0.1" name="k21_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v21</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k21</ci>
<ci>ShP</ci>
<ci>Grb</ci>
</apply>
<apply>
<times/>
<ci>k21_</ci>
<ci>Sh_G</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v22">
<variable name="v22" public_interface="out" units="flux"/>
<variable name="Sh_G_S" public_interface="in" units="nanomolar"/>
<variable name="SOS" public_interface="in" units="nanomolar"/>
<variable name="Sh_G" public_interface="in" units="nanomolar"/>
<variable initial_value="0.03" name="k22" units="second_order_rate_constant"/>
<variable initial_value="0.064" name="k22_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v22</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k22</ci>
<ci>Sh_G</ci>
<ci>SOS</ci>
</apply>
<apply>
<times/>
<ci>k22_</ci>
<ci>Sh_G_S</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v23">
<variable name="v23" public_interface="out" units="flux"/>
<variable name="G_S" public_interface="in" units="nanomolar"/>
<variable name="ShP" public_interface="in" units="nanomolar"/>
<variable name="Sh_G_S" public_interface="in" units="nanomolar"/>
<variable initial_value="0.1" name="k23" units="first_order_rate_constant"/>
<variable initial_value="0.021" name="k23_" units="second_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v23</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k23</ci>
<ci>Sh_G_S</ci>
</apply>
<apply>
<times/>
<ci>k23_</ci>
<ci>ShP</ci>
<ci>G_S</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v24">
<variable name="v24" public_interface="out" units="flux"/>
<variable name="R_Sh_G_S" public_interface="in" units="nanomolar"/>
<variable name="G_S" public_interface="in" units="nanomolar"/>
<variable name="R_ShP" public_interface="in" units="nanomolar"/>
<variable initial_value="0.009" name="k24" units="second_order_rate_constant"/>
<variable initial_value="4.29e-2" name="k24_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v24</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k24</ci>
<ci>R_ShP</ci>
<ci>G_S</ci>
</apply>
<apply>
<times/>
<ci>k24_</ci>
<ci>R_Sh_G_S</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v25">
<variable name="v25" public_interface="out" units="flux"/>
<variable name="PLC_gamma_P" public_interface="in" units="nanomolar"/>
<variable name="PLC_gamma_P_I" public_interface="in" units="nanomolar"/>
<variable initial_value="1" name="k25" units="first_order_rate_constant"/>
<variable initial_value="0.03" name="k25_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v25</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>k25</ci>
<ci>PLC_gamma_P</ci>
</apply>
<apply>
<times/>
<ci>k25_</ci>
<ci>PLC_gamma_P_I</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="combined_concs">
<variable name="totEGFRphos" units="nanomolar"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable name="R_PL" public_interface="in" units="nanomolar"/>
<variable name="R_PLP" public_interface="in" units="nanomolar"/>
<variable name="R_G" public_interface="in" units="nanomolar"/>
<variable name="R_G_S" public_interface="in" units="nanomolar"/>
<variable name="R_Sh" public_interface="in" units="nanomolar"/>
<variable name="R_ShP" public_interface="in" units="nanomolar"/>
<variable name="R_Sh_G" public_interface="in" units="nanomolar"/>
<variable name="R_Sh_G_S" public_interface="in" units="nanomolar"/>
<variable name="totPLCgammaphos" units="nanomolar"/>
<variable name="PLC_gamma_P" public_interface="in" units="nanomolar"/>
<variable name="ShP" public_interface="in" units="nanomolar"/>
<variable name="Sh_G" public_interface="in" units="nanomolar"/>
<variable name="Sh_G_S" public_interface="in" units="nanomolar"/>
<variable name="totGrb_EGFR" units="nanomolar"/>
<variable name="totGrb_Shc" units="nanomolar"/>
<variable name="totShcphos" units="nanomolar"/>
<variable name="totShc_EGFR" units="nanomolar"/>
<variable name="totSOS_EGFR" units="nanomolar"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>totEGFRphos</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<apply>
<plus/>
<ci>RP</ci>
<ci>R_PL</ci>
<ci>R_PLP</ci>
<ci>R_G</ci>
<ci>R_G_S</ci>
<ci>R_Sh</ci>
<ci>R_ShP</ci>
<ci>R_Sh_G</ci>
<ci>R_Sh_G_S</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>totPLCgammaphos</ci>
<apply>
<plus/>
<ci>R_PLP</ci>
<ci>PLC_gamma_P</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>totShcphos</ci>
<apply>
<plus/>
<ci>R_ShP</ci>
<ci>R_Sh_G</ci>
<ci>R_Sh_G_S</ci>
<ci>ShP</ci>
<ci>Sh_G</ci>
<ci>Sh_G_S</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>totGrb_EGFR</ci>
<apply>
<plus/>
<ci>R_G</ci>
<ci>R_G_S</ci>
<ci>R_Sh_G</ci>
<ci>R_Sh_G_S</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>totGrb_Shc</ci>
<apply>
<plus/>
<ci>R_Sh_G</ci>
<ci>Sh_G</ci>
<ci>R_Sh_G_S</ci>
<ci>Sh_G_S</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>totShc_EGFR</ci>
<apply>
<plus/>
<ci>R_ShP</ci>
<ci>R_Sh_G</ci>
<ci>R_Sh_G_S</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>totSOS_EGFR</ci>
<apply>
<plus/>
<ci>R_G_S</ci>
<ci>R_Sh_G_S</ci>
</apply>
</apply>
</math>
</component>
<connection>
<map_components component_1="EGF" component_2="v1"/>
<map_variables variable_1="EGF" variable_2="EGF"/>
<map_variables variable_1="v1" variable_2="v1"/>
</connection>
<connection>
<map_components component_1="R" component_2="v1"/>
<map_variables variable_1="R" variable_2="R"/>
<map_variables variable_1="v1" variable_2="v1"/>
</connection>
<connection>
<map_components component_1="Ra" component_2="v1"/>
<map_variables variable_1="Ra" variable_2="Ra"/>
<map_variables variable_1="v1" variable_2="v1"/>
</connection>
<connection>
<map_components component_1="Ra" component_2="v2"/>
<map_variables variable_1="Ra" variable_2="Ra"/>
<map_variables variable_1="v2" variable_2="v2"/>
</connection>
<connection>
<map_components component_1="R2" component_2="v2"/>
<map_variables variable_1="R2" variable_2="R2"/>
<map_variables variable_1="v2" variable_2="v2"/>
</connection>
<connection>
<map_components component_1="R2" component_2="v3"/>
<map_variables variable_1="R2" variable_2="R2"/>
<map_variables variable_1="v3" variable_2="v3"/>
</connection>
<connection>
<map_components component_1="R2" component_2="v4"/>
<map_variables variable_1="v4" variable_2="v4"/>
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<rdf:value>This model has been recoded in CellML without the use of the reaction element. The parameters and differential equations described in the original publication were used. This file is known to read in both COR and PCEnv and is able to reproduce the graphs in Figure 5 of the Kholodenko et al. 1999 publication.</rdf:value>
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<rdf:value>Removed connection duplications, added component defining total concentrations of various species, inc. EGFR, as used in graphs in figure 5 of publication.</rdf:value>
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