- Author:
- Hanne <Hanne@hanne-nielsens-macbook.local>
- Date:
- 2010-07-22 13:06:45+12:00
- Desc:
- Added xul and session file
- Permanent Source URI:
- https://models.physiomeproject.org/workspace/394/rawfile/341f9f492314f3db1c9a753f4ec45d6e406fc32b/kholodenko_demin_moehren_hoek_1999.cellml
<?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 EGF Receptor Signalling</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 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.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
The epidermal growth factor receptor (EGFR) is a protein-tyrosine kinase receptor which regulates cell growth, survival, proliferation, and differentiation. When epidermal growth factor (EGF) binds to EGFR is causes receptor dimerisation and activates its kinase activity, leading to autophosphorylation. In turn, this leads to a range of cytoplasmic proteins with specific binding domains, binding to the activated EGFR, and then themselves becoming phosphorylated and activated. This then leads to further propagation of the signal through several interacting signal transduction pathways.
</para>
<para>
Although there is a large body of data which describes EGFR signalling at the molecular level, the mechanisms underlying the regulation of the cellular responses to EGF remain poorly understood. A contributing factor to this relatively poor understanding is the absence of a quantitative description of the EGFR signalling network. Placing the experimental data within the framework of a mathematical model provides a method of quantitatively analysing the available experimental data. In the paper described here, Kholodenko <emphasis>et al</emphasis>. develop a mathematical model which presents a quantitative description of short term EGFR signalling (see <xref linkend="fig_reaction_diagram"/> below).
</para>
<para>
The kinetic model predicts how the cellular response is controlled by the relative levels and activity states of the signalling proteins, and also determines the conditions under which activation patterns are transient or sustained. This modelling analysis will facilitate the assessment of how the EGFR signalling system can process information and generate distinct outputs in response to stimuli.
</para>
<para>
The model has been described here in CellML (the raw CellML description of the Kholodenko <emphasis>et al.</emphasis> 1999 model can be downloaded in various formats as described in <xref linkend="sec_download_this_model"/>).
</para>
<para>
The complete 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>
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<caption>Kinetic scheme of EGFR signalling mediated by adapter and target proteins.</caption>
</informalfigure>
</sect1>
</article>
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<ci>Ra</ci>
<ci>Ra</ci>
</apply>
<apply>
<times/>
<ci>k2_</ci>
<ci>R2</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v3">
<variable name="v3" public_interface="out" units="flux"/>
<variable name="R2" public_interface="in" units="nanomolar"/>
<variable name="RP" public_interface="in" units="nanomolar"/>
<variable initial_value="1" name="k3" units="first_order_rate_constant"/>
<variable initial_value="0.01" name="k3_" units="first_order_rate_constant"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v3</ci>
<apply>
<minus/>
<apply>
<times/>
<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"/>
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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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