- Author:
- pmr2.import <nobody@models.cellml.org>
- Date:
- 2006-07-09 07:34:36+12:00
- Desc:
- committing version01 of kholodenko_demin_moehren_hoek_1999
- Permanent Source URI:
- https://models.cellml.org/workspace/394/rawfile/e5e60fb8c0effc84943fa466b899efef36ebcb7f/kholodenko_demin_moehren_hoek_1999.cellml
<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : kholodenko_model_1999.xml
CREATED : 6th October 2003
LAST MODIFIED : 6th October 2003
AUTHOR : Catherine Lloyd
Bioengineering Institute
The University of Auckland
MODEL STATUS : This model conforms to the CellML 1.0 Specification released on
10th August 2001, and the 16/1/02 CellML Metadata 1.0 Specification.
DESCRIPTION : This file contains a CellML description of Kholodenko et al.'s 1999 mathematical model of the kinetics of EGFR signalling.
CHANGES:
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" cmeta:id="kholodenko_demin_moehren_hoek_1999_version01" name="kholodenko_demin_moehren_hoek_1999_version01">
<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 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>
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>
<ulink url="http://www.jbc.org/cgi/content/abstract/274/42/30169">Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor</ulink>, Boris N. Kholodenko, Oleg V. Demin, Gisela Moehren, and Jan B. Hoek, 1999, <ulink url="http://www.jbc.org/">
<emphasis>The Journal of Biological Chemistry</emphasis>
</ulink>, 274, 30169-30181. (<ulink url="http://www.jbc.org/cgi/content/full/274/42/30169">Full text (HTML)</ulink> and <ulink url="http://www.jbc.org/cgi/reprint/274/42/30169.pdf">PDF</ulink> versions of the article are available on <emphasis>The Journal of Biological Chemistry</emphasis> website.) <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">
<mediaobject>
<imageobject>
<objectinfo>
<title>reaction diagram</title>
</objectinfo>
<imagedata fileref="kholodenko_1999.png"/>
</imageobject>
</mediaobject>
<caption>Kinetic scheme of EGFR signalling mediated by adapter and target proteins.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
<units name="nanomolar">
<unit units="mole" prefix="nano"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="flux">
<unit units="nanomolar"/>
<unit units="second" exponent="-1"/>
</units>
<units name="first_order_rate_constant">
<unit units="second" exponent="-1"/>
</units>
<units name="second_order_rate_constant">
<unit units="nanomolar" exponent="-1"/>
<unit units="second" exponent="-1"/>
</units>
<component name="environment">
<variable units="second" public_interface="out" name="time"/>
</component>
<component cmeta:id="EGF" name="EGF">
<rdf:RDF>
<rdf:Description rdf:about="EGF">
<dc:title>EGF</dc:title>
<dcterms:alternative>epidermal growth factor</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="EGF"/>
<variable units="flux" public_interface="in" name="v1"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>EGF</ci>
</apply>
<apply>
<minus/>
<ci>v1</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="R" name="R">
<rdf:RDF>
<rdf:Description rdf:about="R">
<dc:title>R</dc:title>
<dcterms:alternative>epidermal growth factor receptor</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R"/>
<variable units="flux" public_interface="in" name="v1"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R</ci>
</apply>
<apply>
<minus/>
<ci>v1</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="Ra" name="Ra">
<rdf:RDF>
<rdf:Description rdf:about="Ra">
<dc:title>Ra</dc:title>
<dcterms:alternative>EGF-EGFR complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="Ra"/>
<variable units="flux" public_interface="in" name="v1"/>
<variable units="flux" public_interface="in" name="v2"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ra</ci>
</apply>
<apply>
<minus/>
<ci>v1</ci>
<apply>
<times/>
<cn cellml:units="dimensionless"> 2.0 </cn>
<ci>v2</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="R2" name="R2">
<rdf:RDF>
<rdf:Description rdf:about="R2">
<dc:title>R2</dc:title>
<dcterms:alternative>EGF-EGFR complex dimer</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R2"/>
<variable units="flux" public_interface="in" name="v2"/>
<variable units="flux" public_interface="in" name="v3"/>
<variable units="flux" public_interface="in" name="v4"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R2</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v2</ci>
<ci>v4</ci>
</apply>
<ci>v3</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="RP" name="RP">
<rdf:RDF>
<rdf:Description rdf:about="RP">
<dc:title>RP</dc:title>
<dcterms:alternative>phosphorylated EGF-EGFR complex dimer</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="RP"/>
<variable units="flux" public_interface="in" name="v3"/>
<variable units="flux" public_interface="in" name="v7"/>
<variable units="flux" public_interface="in" name="v11"/>
<variable units="flux" public_interface="in" name="v15"/>
<variable units="flux" public_interface="in" name="v18"/>
<variable units="flux" public_interface="in" name="v20"/>
<variable units="flux" public_interface="in" name="v4"/>
<variable units="flux" public_interface="in" name="v5"/>
<variable units="flux" public_interface="in" name="v9"/>
<variable units="flux" public_interface="in" name="v13"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>RP</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v3</ci>
<ci>v7</ci>
<ci>v11</ci>
<ci>v15</ci>
<ci>v18</ci>
<ci>v20</ci>
</apply>
<apply>
<plus/>
<ci>v4</ci>
<ci>v5</ci>
<ci>v9</ci>
<ci>v13</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="R_PL" name="R_PL">
<rdf:RDF>
<rdf:Description rdf:about="R_PL">
<dc:title>R_PL</dc:title>
<dcterms:alternative>phosphorylated EGF-EGFR-PLC complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R_PL"/>
<variable units="flux" public_interface="in" name="v5"/>
<variable units="flux" public_interface="in" name="v6"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_PL</ci>
</apply>
<apply>
<minus/>
<ci>v5</ci>
<ci>v6</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="R_PLP" name="R_PLP">
<rdf:RDF>
<rdf:Description rdf:about="R_PLP">
<dc:title>R_PLP</dc:title>
<dcterms:alternative>double phosphorylated EGF-EGFR-PLC complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R_PLP"/>
<variable units="flux" public_interface="in" name="v6"/>
<variable units="flux" public_interface="in" name="v7"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_PLP</ci>
</apply>
<apply>
<minus/>
<ci>v6</ci>
<ci>v7</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="R_G" name="R_G">
<rdf:RDF>
<rdf:Description rdf:about="R_G">
<dc:title>R_G</dc:title>
<dcterms:alternative>phosphotyrosine-Grb2 complex</dcterms:alternative> </rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R_G"/>
<variable units="flux" public_interface="in" name="v9"/>
<variable units="flux" public_interface="in" name="v10"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_G</ci>
</apply>
<apply>
<minus/>
<ci>v9</ci>
<ci>v10</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="R_G_S" name="R_G_S">
<rdf:RDF>
<rdf:Description rdf:about="R_G_S">
<dc:title>R_G_S</dc:title>
<dcterms:alternative>phosphotyrosine-Grb2-SOS complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R_G_S"/>
<variable units="flux" public_interface="in" name="v10"/>
<variable units="flux" public_interface="in" name="v11"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_G_S</ci>
</apply>
<apply>
<minus/>
<ci>v10</ci>
<ci>v11</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="R_Sh" name="R_Sh">
<rdf:RDF>
<rdf:Description rdf:about="R_Sh">
<dc:title>R_Sh</dc:title>
<dcterms:alternative>EGFR-Shc complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R_Sh"/>
<variable units="flux" public_interface="in" name="v13"/>
<variable units="flux" public_interface="in" name="v14"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_Sh</ci>
</apply>
<apply>
<minus/>
<ci>v13</ci>
<ci>v14</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="R_ShP" name="R_ShP">
<rdf:RDF>
<rdf:Description rdf:about="R_ShP">
<dc:title>R_ShP</dc:title>
<dcterms:alternative>phosphorylated EGFR-Shc complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R_ShP"/>
<variable units="flux" public_interface="in" name="v14"/>
<variable units="flux" public_interface="in" name="v24"/>
<variable units="flux" public_interface="in" name="v15"/>
<variable units="flux" public_interface="in" name="v17"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_ShP</ci>
</apply>
<apply>
<minus/>
<ci>v14</ci>
<apply>
<plus/>
<ci>v24</ci>
<ci>v15</ci>
<ci>v17</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="R_Sh_G" name="R_Sh_G">
<rdf:RDF>
<rdf:Description rdf:about="R_Sh_G">
<dc:title>R_Sh_G</dc:title>
<dcterms:alternative>EGFR-Shc-Grb2 complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R_Sh_G"/>
<variable units="flux" public_interface="in" name="v17"/>
<variable units="flux" public_interface="in" name="v18"/>
<variable units="flux" public_interface="in" name="v19"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_Sh_G</ci>
</apply>
<apply>
<minus/>
<ci>v17</ci>
<apply>
<plus/>
<ci>v18</ci>
<ci>v19</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="R_Sh_G_S" name="R_Sh_G_S">
<rdf:RDF>
<rdf:Description rdf:about="R_Sh_G_S">
<dc:title>R_Sh_G_S</dc:title>
<dcterms:alternative>EGFR-Shc-Grb2-SOS complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="R_Sh_G_S"/>
<variable units="flux" public_interface="in" name="v19"/>
<variable units="flux" public_interface="in" name="v20"/>
<variable units="flux" public_interface="in" name="v24"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_Sh_G_S</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v19</ci>
<ci>v24</ci>
</apply>
<ci>v20</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="G_S" name="G_S">
<rdf:RDF>
<rdf:Description rdf:about="G_S">
<dc:title>G_S</dc:title>
<dcterms:alternative>Grb2-SOS complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="G_S"/>
<variable units="flux" public_interface="in" name="v11"/>
<variable units="flux" public_interface="in" name="v23"/>
<variable units="flux" public_interface="in" name="v12"/>
<variable units="flux" public_interface="in" name="v24"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>G_S</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v11</ci>
<ci>v23</ci>
</apply>
<apply>
<plus/>
<ci>v12</ci>
<ci>v24</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="ShP" name="ShP">
<rdf:RDF>
<rdf:Description rdf:about="ShP">
<dc:title>ShP</dc:title>
<dcterms:alternative>phosphorylated Shc</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="ShP"/>
<variable units="flux" public_interface="in" name="v15"/>
<variable units="flux" public_interface="in" name="v23"/>
<variable units="flux" public_interface="in" name="v21"/>
<variable units="flux" public_interface="in" name="v16"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>ShP</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v15</ci>
<ci>v23</ci>
</apply>
<apply>
<plus/>
<ci>v21</ci>
<ci>v16</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="Sh_G" name="Sh_G">
<rdf:RDF>
<rdf:Description rdf:about="Sh_G">
<dc:title>Sh_G</dc:title>
<dcterms:alternative>Shc-Grb2 complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="Sh_G"/>
<variable units="flux" public_interface="in" name="v18"/>
<variable units="flux" public_interface="in" name="v21"/>
<variable units="flux" public_interface="in" name="v22"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Sh_G</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v18</ci>
<ci>v21</ci>
</apply>
<ci>v22</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="Sh_G_S" name="Sh_G_S">
<rdf:RDF>
<rdf:Description rdf:about="Sh_G_S">
<dc:title>Sh_G_S</dc:title>
<dcterms:alternative>Shc-Grb2-SOS complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="Sh_G_S"/>
<variable units="flux" public_interface="in" name="v20"/>
<variable units="flux" public_interface="in" name="v22"/>
<variable units="flux" public_interface="in" name="v23"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Sh_G_S</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v20</ci>
<ci>v22</ci>
</apply>
<ci>v23</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="PLC_gamma" name="PLC_gamma">
<rdf:RDF>
<rdf:Description rdf:about="PLC_gamma">
<dc:title>PLC_gamma</dc:title>
<dcterms:alternative>phospholipase C-gamma</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="PLC_gamma"/>
<variable units="flux" public_interface="in" name="v8"/>
<variable units="flux" public_interface="in" name="v5"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>PLC_gamma</ci>
</apply>
<apply>
<minus/>
<ci>v8</ci>
<ci>v5</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="PLC_gamma_P" name="PLC_gamma_P">
<rdf:RDF>
<rdf:Description rdf:about="PLC_gamma_P">
<dc:title>PLC_gamma_P</dc:title>
<dcterms:alternative>phosphorylated phospholipase C-gamma</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="PLC_gamma_P"/>
<variable units="flux" public_interface="in" name="v7"/>
<variable units="flux" public_interface="in" name="v8"/>
<variable units="flux" public_interface="in" name="v25"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>PLC_gamma_P</ci>
</apply>
<apply>
<minus/>
<ci>v7</ci>
<apply>
<plus/>
<ci>v8</ci>
<ci>v25</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="PLC_gamma_P_I" name="PLC_gamma_P_I">
<rdf:RDF>
<rdf:Description rdf:about="PLC_gamma_P_I">
<dc:title>PLC_gamma_P_I</dc:title>
<dcterms:alternative>bound phosphorylated phospholipase C-gamma</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="PLC_gamma_P_I"/>
<variable units="flux" public_interface="in" name="v25"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>PLC_gamma_P_I</ci>
</apply>
<ci>v25</ci>
</apply>
</math>
</component>
<component cmeta:id="Grb" name="Grb">
<rdf:RDF>
<rdf:Description rdf:about="Grb">
<dc:title>Grb</dc:title>
<dcterms:alternative>growth factor receptor-binding protein 2</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="Grb"/>
<variable units="flux" public_interface="in" name="v12"/>
<variable units="flux" public_interface="in" name="v9"/>
<variable units="flux" public_interface="in" name="v17"/>
<variable units="flux" public_interface="in" name="v21"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Grb</ci>
</apply>
<apply>
<minus/>
<ci>v12</ci>
<apply>
<plus/>
<ci>v9</ci>
<ci>v17</ci>
<ci>v21</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="Shc" name="Shc">
<rdf:RDF>
<rdf:Description rdf:about="Shc">
<dc:title>Shc</dc:title>
<dcterms:alternative>Src homology and collagen domain protein</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="Shc"/>
<variable units="flux" public_interface="in" name="v16"/>
<variable units="flux" public_interface="in" name="v13"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Shc</ci>
</apply>
<apply>
<minus/>
<ci>v16</ci>
<ci>v13</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="SOS" name="SOS">
<rdf:RDF>
<rdf:Description rdf:about="SOS">
<dc:title>SOS</dc:title>
<dcterms:alternative>Son of Sevenless homolog protein</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="nanomolar" public_interface="out" name="SOS"/>
<variable units="flux" public_interface="in" name="v12"/>
<variable units="flux" public_interface="in" name="v10"/>
<variable units="flux" public_interface="in" name="v19"/>
<variable units="flux" public_interface="in" name="v22"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>SOS</ci>
</apply>
<apply>
<minus/>
<ci>v12</ci>
<apply>
<plus/>
<ci>v10</ci>
<ci>v19</ci>
<ci>v22</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v1">
<variable units="flux" public_interface="out" name="v1"/>
<variable units="nanomolar" public_interface="in" name="R"/>
<variable units="nanomolar" public_interface="in" name="EGF"/>
<variable units="nanomolar" public_interface="in" name="Ra"/>
<variable units="second_order_rate_constant" name="k1" initial_value="0.003"/>
<variable units="first_order_rate_constant" name="k1_" initial_value="0.06"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v1_calculation">
<eq/>
<ci> v1 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k1 </ci>
<ci> R </ci>
<ci> EGF </ci>
</apply>
<apply>
<times/>
<ci> k1_ </ci>
<ci> Ra </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v2">
<variable units="flux" public_interface="out" name="v2"/>
<variable units="nanomolar" public_interface="in" name="R2"/>
<variable units="nanomolar" public_interface="in" name="Ra"/>
<variable units="second_order_rate_constant" name="k2" initial_value="0.01"/>
<variable units="first_order_rate_constant" name="k2_" initial_value="0.1"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v2_calculation">
<eq/>
<ci> v2 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k2 </ci>
<ci> Ra </ci>
<ci> Ra </ci>
</apply>
<apply>
<times/>
<ci> k2_ </ci>
<ci> R2 </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v3">
<variable units="flux" public_interface="out" name="v3"/>
<variable units="nanomolar" public_interface="in" name="R2"/>
<variable units="nanomolar" public_interface="in" name="RP"/>
<variable units="first_order_rate_constant" name="k3" initial_value="1.0"/>
<variable units="first_order_rate_constant" name="k3_" initial_value="0.01"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v3_calculation">
<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 units="flux" public_interface="out" name="v4"/>
<variable units="nanomolar" public_interface="in" name="RP"/>
<variable units="nanomolar" name="K4" initial_value="50.0"/>
<variable units="flux" name="V4" initial_value="450.0"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v4_calculation">
<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 units="flux" public_interface="out" name="v5"/>
<variable units="nanomolar" public_interface="in" name="R_PL"/>
<variable units="nanomolar" public_interface="in" name="PLC_gamma"/>
<variable units="nanomolar" public_interface="in" name="RP"/>
<variable units="second_order_rate_constant" name="k5" initial_value="0.06"/>
<variable units="first_order_rate_constant" name="k5_" initial_value="0.2"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v5_calculation">
<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 units="flux" public_interface="out" name="v6"/>
<variable units="nanomolar" public_interface="in" name="R_PL"/>
<variable units="nanomolar" public_interface="in" name="R_PLP"/>
<variable units="first_order_rate_constant" name="k6" initial_value="1.0"/>
<variable units="first_order_rate_constant" name="k6_" initial_value="0.05"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v6_calculation">
<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 units="flux" public_interface="out" name="v7"/>
<variable units="nanomolar" public_interface="in" name="R_PLP"/>
<variable units="nanomolar" public_interface="in" name="PLC_gamma_P"/>
<variable units="nanomolar" public_interface="in" name="RP"/>
<variable units="first_order_rate_constant" name="k7" initial_value="0.06"/>
<variable units="second_order_rate_constant" name="k7_" initial_value="0.2"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v7_calculation">
<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 units="flux" public_interface="out" name="v8"/>
<variable units="nanomolar" public_interface="in" name="PLC_gamma_P"/>
<variable units="nanomolar" name="K8" initial_value="100.0"/>
<variable units="flux" name="V8" initial_value="1.0"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v8_calculation">
<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 units="flux" public_interface="out" name="v9"/>
<variable units="nanomolar" public_interface="in" name="R_G"/>
<variable units="nanomolar" public_interface="in" name="Grb"/>
<variable units="nanomolar" public_interface="in" name="RP"/>
<variable units="second_order_rate_constant" name="k9" initial_value="0.003"/>
<variable units="first_order_rate_constant" name="k9_" initial_value="0.05"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v9_calculation">
<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 units="flux" public_interface="out" name="v10"/>
<variable units="nanomolar" public_interface="in" name="R_G_S"/>
<variable units="nanomolar" public_interface="in" name="SOS"/>
<variable units="nanomolar" public_interface="in" name="R_G"/>
<variable units="second_order_rate_constant" name="k10" initial_value="0.01"/>
<variable units="first_order_rate_constant" name="k10_" initial_value="0.06"/>
<math xmlns="http://www.w3.org/110108/Math/MathML">
<apply id="v10_calculation">
<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 units="flux" public_interface="out" name="v11"/>
<variable units="nanomolar" public_interface="in" name="R_G_S"/>
<variable units="nanomolar" public_interface="in" name="G_S"/>
<variable units="nanomolar" public_interface="in" name="RP"/>
<variable units="first_order_rate_constant" name="k11" initial_value="0.03"/>
<variable units="second_order_rate_constant" name="k11_" initial_value="4.5E-3"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v11_calculation">
<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 units="flux" public_interface="out" name="v12"/>
<variable units="nanomolar" public_interface="in" name="G_S"/>
<variable units="nanomolar" public_interface="in" name="SOS"/>
<variable units="nanomolar" public_interface="in" name="Grb"/>
<variable units="first_order_rate_constant" name="k12" initial_value="1.5E-3"/>
<variable units="second_order_rate_constant" name="k12_" initial_value="1.0E-4"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v12_calculation">
<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 units="flux" public_interface="out" name="v13"/>
<variable units="nanomolar" public_interface="in" name="R_Sh"/>
<variable units="nanomolar" public_interface="in" name="Shc"/>
<variable units="nanomolar" public_interface="in" name="RP"/>
<variable units="second_order_rate_constant" name="k13" initial_value="0.09"/>
<variable units="first_order_rate_constant" name="k13_" initial_value="0.6"/>
<math xmlns="http://www.w3.org/113138/Math/MathML">
<apply id="v13_calculation">
<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 units="flux" public_interface="out" name="v14"/>
<variable units="nanomolar" public_interface="in" name="R_Sh"/>
<variable units="nanomolar" public_interface="in" name="R_ShP"/>
<variable units="first_order_rate_constant" name="k14" initial_value="6.0"/>
<variable units="first_order_rate_constant" name="k14_" initial_value="0.06"/>
<math xmlns="http://www.w3.org/114148/Math/MathML">
<apply id="v14_calculation">
<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 units="flux" public_interface="out" name="v15"/>
<variable units="nanomolar" public_interface="in" name="R_ShP"/>
<variable units="nanomolar" public_interface="in" name="RP"/>
<variable units="nanomolar" public_interface="in" name="ShP"/>
<variable units="first_order_rate_constant" name="k15" initial_value="0.3"/>
<variable units="second_order_rate_constant" name="k15_" initial_value="9.0E-4"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v15_calculation">
<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 units="flux" public_interface="out" name="v16"/>
<variable units="nanomolar" public_interface="in" name="ShP"/>
<variable units="nanomolar" name="K16" initial_value="340.0"/>
<variable units="flux" name="V16" initial_value="1.7"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v16_calculation">
<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 units="flux" public_interface="out" name="v17"/>
<variable units="nanomolar" public_interface="in" name="R_ShP"/>
<variable units="nanomolar" public_interface="in" name="Grb"/>
<variable units="nanomolar" public_interface="in" name="R_Sh_G"/>
<variable units="second_order_rate_constant" name="k17" initial_value="0.003"/>
<variable units="first_order_rate_constant" name="k17_" initial_value="0.1"/>
<math xmlns="http://www.w3.org/117178/Math/MathML">
<apply id="v17_calculation">
<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 units="flux" public_interface="out" name="v18"/>
<variable units="nanomolar" public_interface="in" name="R_Sh_G"/>
<variable units="nanomolar" public_interface="in" name="RP"/>
<variable units="nanomolar" public_interface="in" name="Sh_G"/>
<variable units="first_order_rate_constant" name="k18" initial_value="0.3"/>
<variable units="second_order_rate_constant" name="k18_" initial_value="9.0E-4"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v18_calculation">
<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 units="flux" public_interface="out" name="v19"/>
<variable units="nanomolar" public_interface="in" name="R_Sh_G_S"/>
<variable units="nanomolar" public_interface="in" name="SOS"/>
<variable units="nanomolar" public_interface="in" name="R_Sh_G"/>
<variable units="second_order_rate_constant" name="k19" initial_value="0.01"/>
<variable units="first_order_rate_constant" name="k19_" initial_value="2.14E-2"/>
<math xmlns="http://www.w3.org/119198/Math/MathML">
<apply id="v19_calculation">
<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 units="flux" public_interface="out" name="v20"/>
<variable units="nanomolar" public_interface="in" name="Sh_G_S"/>
<variable units="nanomolar" public_interface="in" name="RP"/>
<variable units="nanomolar" public_interface="in" name="R_Sh_G_S"/>
<variable units="first_order_rate_constant" name="k20" initial_value="0.12"/>
<variable units="second_order_rate_constant" name="k20_" initial_value="2.4E-4"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="v20_calculation">
<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 units="flux" public_interface="out" name="v21"/>
<variable units="nanomolar" public_interface="in" name="Sh_G"/>
<variable units="nanomolar" public_interface="in" name="Grb"/>
<variable units="nanomolar" public_interface="in" name="ShP"/>
<variable units="second_order_rate_constant" name="k21" initial_value="0.003"/>
<variable units="first_order_rate_constant" name="k21_" initial_value="0.1"/>
<math xmlns="http://www.w3.org/121218/Math/MathML">
<apply id="v21_calculation">
<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 units="flux" public_interface="out" name="v22"/>
<variable units="nanomolar" public_interface="in" name="Sh_G_S"/>
<variable units="nanomolar" public_interface="in" name="SOS"/>
<variable units="nanomolar" public_interface="in" name="Sh_G"/>
<variable units="second_order_rate_constant" name="k22" initial_value="0.03"/>
<variable units="first_order_rate_constant" name="k22_" initial_value="0.064"/>
<math xmlns="http://www.w3.org/122228/Math/MathML">
<apply id="v22_calculation">
<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 units="flux" public_interface="out" name="v23"/>
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Kholodenko et al.'s 1999 mathematical model of the kinetics of EGFR
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Quantification of short term signalling by the epidermal growth
factor receptor
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This is the CellML description of Kholodenko et al.'s 1999
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The University of Auckland, Bioengineering Institute
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