<?xml version='1.0' encoding='utf-8'?>
<!--
This CellML file was generated on 20/06/2007 at 12:39:18 at a.m. using:
COR (0.9.31.649)
Copyright 2002-2007 Dr Alan Garny
http://COR.physiol.ox.ac.uk/ - COR@physiol.ox.ac.uk
CellML 1.0 was used to generate this cellular model
http://www.CellML.org/
--><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="bhalla_model_1999" name="hatakeyama_model_2003">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB 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 version of the model has been checked in COR and PCEnv and it runs to replicate the published results. The units have been checked and they are consistent.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ErbB receptor tyrosine kinases play an essential role in the proliferation and differentiation of cells. The ErbB receptor family includes ErbB1 - also known as the epidermal growth factor receptor (EGFR) - and the signalling pathways which involve this receptor have been extensively analysed, both experimentally and also via mathematical modelling. ErbB receptors share a common ability to bind a diverse range of ligands, in turn producing a wide range of biological responses. In the study described here, Mariko Hatakeyama <emphasis>et al.</emphasis> examined heregulin (HRG)-induced signal transduction of the ErbB4 receptor, and they produced a mathematical model to capture the features of the signal transduction cascade (described in more detail in the figure below). This model is described here in CellML.
</para>
<para>
The complete original paper reference is cited below:
</para>
<para>
<ulink url="http://www.biochemj.org/bj/373/bj3730451.htm">A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling</ulink>, Mariko Hatakeyama, Shuhei Kimura, Takashi Naka, Takuji Kawasaki, Noriko Yumoto, Mio Ichikawa, Jae-Hoon Kim, Kazuki Saito, Mihoro Saeki, Mikako Shirouzu, Shigeyuki Yokoyama, and Akihiko Konagaya, 2003, <ulink url="http://www.biochemj.org/bj/">
<emphasis>The Biochemical Journal</emphasis>
</ulink>, 373, 451-463. (<ulink url="http://www.biochemj.org/bj/373/0451/bj3730451.htm">Full text</ulink> and <ulink url="http://www.biochemj.org/bj/373/0451/3730451.pdf">PDF</ulink> versions of the article are available to journal subscribers on <emphasis>The Biochemical Journal</emphasis> website.) <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12691603&dopt=Abstract">PubMed ID: 12691603</ulink>
</para>
<informalfigure float="0" id="fig_pathway_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
</objectinfo>
<imagedata fileref="hatakeyama_networkdiagram_scaled_2003.png"/>
</imageobject>
</mediaobject>
<caption>A schematic diagram of the complete signalling network.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
<units name="s">
<unit units="second"/>
</units>
<units name="nm">
<unit units="mole" prefix="nano"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="flux">
<unit units="nm"/>
<unit units="s" exponent="-1"/>
</units>
<units name="second_order_rate_constant">
<unit units="nm" exponent="-1"/>
<unit units="s" exponent="-1"/>
</units>
<units name="first_order_rate_constant">
<unit units="s" exponent="-1"/>
</units>
<component name="environment">
<variable units="s" public_interface="out" name="time"/>
</component>
<component name="PI3K">
<variable units="s" public_interface="in" name="time"/>
<variable units="second_order_rate_constant" name="kf1" initial_value="0.0012"/>
<variable units="first_order_rate_constant" name="kb1" initial_value="0.00076"/>
<variable units="second_order_rate_constant" name="kf2" initial_value="0.01"/>
<variable units="first_order_rate_constant" name="kb2" initial_value="0.1"/>
<variable units="first_order_rate_constant" name="kf3" initial_value="1"/>
<variable units="first_order_rate_constant" name="kb3" initial_value="0.01"/>
<variable units="first_order_rate_constant" name="kf34" initial_value="0.001"/>
<variable units="first_order_rate_constant" name="kb34" initial_value="0"/>
<variable units="flux" name="V4" initial_value="62.5"/>
<variable units="nm" name="k4" initial_value="50"/>
<variable units="second_order_rate_constant" name="kf5" initial_value="0.1"/>
<variable units="first_order_rate_constant" name="kb5" initial_value="1"/>
<variable units="first_order_rate_constant" name="kf6" initial_value="20"/>
<variable units="first_order_rate_constant" name="kb6" initial_value="5"/>
<variable units="first_order_rate_constant" name="kf7" initial_value="60"/>
<variable units="first_order_rate_constant" name="kb7" initial_value="546"/>
<variable units="first_order_rate_constant" name="kf8" initial_value="2040"/>
<variable units="second_order_rate_constant" name="kb8" initial_value="15700"/>
<variable units="first_order_rate_constant" name="kf9" initial_value="40.8"/>
<variable units="second_order_rate_constant" name="kb9" initial_value="0"/>
<variable units="flux" name="V10" initial_value="0.0154"/>
<variable units="nm" name="k10" initial_value="340"/>
<variable units="second_order_rate_constant" name="kf23" initial_value="0.1"/>
<variable units="first_order_rate_constant" name="kb23" initial_value="2"/>
<variable units="first_order_rate_constant" name="kf24" initial_value="9.85"/>
<variable units="first_order_rate_constant" name="kb24" initial_value="0.0985"/>
<variable units="first_order_rate_constant" name="kf25" initial_value="45.8"/>
<variable units="second_order_rate_constant" name="kb25" initial_value="0.047"/>
<variable units="flux" name="V26" initial_value="2620"/>
<variable units="nm" name="k26" initial_value="3680"/>
<variable units="nm" name="R" initial_value="80"/>
<variable units="nm" name="Shc" initial_value="1000"/>
<variable units="nm" name="PI3K" initial_value="10"/>
<variable units="nm" name="HRG" initial_value="10"/>
<variable units="nm" name="R_HRG" initial_value="0"/>
<variable units="nm" name="R_HRG2" initial_value="0"/>
<variable units="nm" name="Internalisation" initial_value="0"/>
<variable units="nm" name="RP" initial_value="0"/>
<variable units="nm" name="R_Shc" initial_value="0"/>
<variable units="nm" name="R_ShP" initial_value="0"/>
<variable units="nm" name="ShP" initial_value="0"/>
<variable units="nm" name="R_ShGS" initial_value="0"/>
<variable units="nm" public_interface="out" name="ShGS" initial_value="0"/>
<variable units="nm" name="GS" initial_value="10"/>
<variable units="nm" name="R_PI3K" initial_value="0"/>
<variable units="nm" name="R_PI3Kstar" initial_value="0"/>
<variable units="nm" public_interface="out" name="PI3Kstar" initial_value="0"/>
<variable units="dimensionless" name="two" initial_value="2"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<apply>
<minus/>
<ci>kf1</ci>
</apply>
<ci>R</ci>
<ci>HRG</ci>
</apply>
<apply>
<times/>
<ci>kb1</ci>
<ci>R_HRG</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>HRG</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<apply>
<minus/>
<ci>kf1</ci>
</apply>
<ci>R</ci>
<ci>HRG</ci>
</apply>
<apply>
<times/>
<ci>kb1</ci>
<ci>R_HRG</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_HRG</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf1</ci>
<ci>R</ci>
<ci>HRG</ci>
</apply>
<apply>
<times/>
<ci>kb1</ci>
<ci>R_HRG</ci>
</apply>
</apply>
<apply>
<times/>
<ci>two</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>kf2</ci>
<ci>R_HRG</ci>
<ci>R_HRG</ci>
</apply>
<apply>
<times/>
<ci>kb2</ci>
<ci>R_HRG2</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_HRG2</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf2</ci>
<ci>R_HRG</ci>
<ci>R_HRG</ci>
</apply>
<apply>
<times/>
<ci>kb2</ci>
<ci>R_HRG2</ci>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf3</ci>
<ci>R_HRG2</ci>
</apply>
<apply>
<times/>
<ci>kb3</ci>
<ci>RP</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>V4</ci>
<ci>RP</ci>
</apply>
<apply>
<plus/>
<ci>k4</ci>
<ci>RP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>RP</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf3</ci>
<ci>R_HRG2</ci>
</apply>
<apply>
<times/>
<ci>kb3</ci>
<ci>RP</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>V4</ci>
<ci>RP</ci>
</apply>
<apply>
<plus/>
<ci>k4</ci>
<ci>RP</ci>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf5</ci>
<ci>RP</ci>
<ci>Shc</ci>
</apply>
<apply>
<times/>
<ci>kb5</ci>
<ci>R_Shc</ci>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf8</ci>
<ci>R_ShP</ci>
</apply>
<apply>
<times/>
<ci>kb8</ci>
<ci>ShGS</ci>
<ci>RP</ci>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf23</ci>
<ci>RP</ci>
<ci>PI3K</ci>
</apply>
<apply>
<times/>
<ci>kb23</ci>
<ci>R_PI3K</ci>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf25</ci>
<ci>R_PI3Kstar</ci>
</apply>
<apply>
<times/>
<ci>kb25</ci>
<ci>RP</ci>
<ci>PI3Kstar</ci>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf34</ci>
<ci>RP</ci>
</apply>
<apply>
<times/>
<ci>kb34</ci>
<ci>Internalisation</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Internalisation</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf34</ci>
<ci>RP</ci>
</apply>
<apply>
<times/>
<ci>kb34</ci>
<ci>Internalisation</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_Shc</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf5</ci>
<ci>RP</ci>
<ci>Shc</ci>
</apply>
<apply>
<times/>
<ci>kb5</ci>
<ci>R_Shc</ci>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf6</ci>
<ci>R_Shc</ci>
</apply>
<apply>
<times/>
<ci>kb6</ci>
<ci>R_ShP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Shc</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf5</ci>
<ci>RP</ci>
<ci>Shc</ci>
</apply>
<apply>
<times/>
<ci>kb5</ci>
<ci>R_Shc</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>V10</ci>
<ci>ShP</ci>
</apply>
<apply>
<plus/>
<ci>k10</ci>
<ci>ShP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_ShP</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf6</ci>
<ci>R_Shc</ci>
</apply>
<apply>
<times/>
<ci>kb6</ci>
<ci>R_ShP</ci>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf7</ci>
<ci>R_ShP</ci>
</apply>
<apply>
<times/>
<ci>kb7</ci>
<ci>R_ShGS</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>GS</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf7</ci>
<ci>R_ShP</ci>
</apply>
<apply>
<times/>
<ci>kb7</ci>
<ci>R_ShGS</ci>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf9</ci>
<ci>ShGS</ci>
</apply>
<apply>
<times/>
<ci>kb9</ci>
<ci>GS</ci>
<ci>ShP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>ShP</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf9</ci>
<ci>ShGS</ci>
</apply>
<apply>
<times/>
<ci>kb9</ci>
<ci>GS</ci>
<ci>ShP</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>V10</ci>
<ci>ShP</ci>
</apply>
<apply>
<plus/>
<ci>k10</ci>
<ci>ShP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_ShGS</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf7</ci>
<ci>R_ShP</ci>
</apply>
<apply>
<times/>
<ci>kb7</ci>
<ci>R_ShGS</ci>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf8</ci>
<ci>R_ShP</ci>
</apply>
<apply>
<times/>
<ci>kb8</ci>
<ci>ShGS</ci>
<ci>RP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>ShGS</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf8</ci>
<ci>R_ShP</ci>
</apply>
<apply>
<times/>
<ci>kb8</ci>
<ci>ShGS</ci>
<ci>RP</ci>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf9</ci>
<ci>ShGS</ci>
</apply>
<apply>
<times/>
<ci>kb9</ci>
<ci>GS</ci>
<ci>ShP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_PI3K</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf23</ci>
<ci>RP</ci>
<ci>PI3K</ci>
</apply>
<apply>
<times/>
<ci>kb23</ci>
<ci>R_PI3K</ci>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf24</ci>
<ci>R_PI3K</ci>
</apply>
<apply>
<times/>
<ci>kb24</ci>
<ci>R_PI3Kstar</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>PI3K</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf23</ci>
<ci>RP</ci>
<ci>PI3K</ci>
</apply>
<apply>
<times/>
<ci>kb23</ci>
<ci>R_PI3K</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>V26</ci>
<ci>PI3Kstar</ci>
</apply>
<apply>
<plus/>
<ci>k26</ci>
<ci>PI3Kstar</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>R_PI3Kstar</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf24</ci>
<ci>R_PI3K</ci>
</apply>
<apply>
<times/>
<ci>kb24</ci>
<ci>R_PI3Kstar</ci>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf25</ci>
<ci>R_PI3Kstar</ci>
</apply>
<apply>
<times/>
<ci>kb25</ci>
<ci>RP</ci>
<ci>PI3Kstar</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>PI3Kstar</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf25</ci>
<ci>R_PI3Kstar</ci>
</apply>
<apply>
<times/>
<ci>kb25</ci>
<ci>RP</ci>
<ci>PI3Kstar</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>V26</ci>
<ci>PI3Kstar</ci>
</apply>
<apply>
<plus/>
<ci>k26</ci>
<ci>PI3Kstar</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="RasGDPtoRasGTP">
<variable units="s" public_interface="in" name="time"/>
<variable units="nm" public_interface="in" name="ShGS"/>
<variable units="nm" public_interface="out" name="RasGTP" initial_value="0"/>
<variable units="first_order_rate_constant" name="kf11" initial_value="0.222"/>
<variable units="nm" name="k11" initial_value="0.181"/>
<variable units="flux" name="V12" initial_value="0.289"/>
<variable units="nm" name="k12" initial_value="0.0571"/>
<variable units="nm" name="RasGDP" initial_value="120"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>RasGDP</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>kf11</ci>
<ci>ShGS</ci>
<ci>RasGDP</ci>
</apply>
<apply>
<plus/>
<ci>k11</ci>
<ci>RasGDP</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>V12</ci>
<ci>RasGTP</ci>
</apply>
<apply>
<plus/>
<ci>k12</ci>
<ci>RasGTP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>RasGTP</ci>
</apply>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>kf11</ci>
<ci>ShGS</ci>
<ci>RasGDP</ci>
</apply>
<apply>
<plus/>
<ci>k11</ci>
<ci>RasGDP</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>V12</ci>
<ci>RasGTP</ci>
</apply>
<apply>
<plus/>
<ci>k12</ci>
<ci>RasGTP</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="RAF">
<variable units="s" public_interface="in" name="time"/>
<variable units="nm" public_interface="in" name="RasGTP"/>
<variable units="nm" public_interface="in" name="Akt_PIPP"/>
<variable units="nm" public_interface="out" name="RAF_star" initial_value="100"/>
<variable units="first_order_rate_constant" name="kf13" initial_value="1.53"/>
<variable units="nm" name="k13" initial_value="11.7"/>
<variable units="first_order_rate_constant" name="kf14" initial_value="0.00673"/>
<variable units="nm" name="k14" initial_value="8.07"/>
<variable units="nm" name="E" initial_value="7"/>
<variable units="nm" name="RAF" initial_value="0"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>RAF</ci>
</apply>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>kf14</ci>
<apply>
<plus/>
<ci>Akt_PIPP</ci>
<ci>E</ci>
</apply>
<ci>RAF_star</ci>
</apply>
<apply>
<plus/>
<ci>k14</ci>
<ci>RAF_star</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf13</ci>
<ci>RasGTP</ci>
<ci>RAF</ci>
</apply>
<apply>
<plus/>
<ci>k13</ci>
<ci>RAF</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>RAF_star</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>kf14</ci>
<apply>
<plus/>
<ci>Akt_PIPP</ci>
<ci>E</ci>
</apply>
<ci>RAF_star</ci>
</apply>
<apply>
<plus/>
<ci>k14</ci>
<ci>RAF_star</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf13</ci>
<ci>RasGTP</ci>
<ci>RAF</ci>
</apply>
<apply>
<plus/>
<ci>k13</ci>
<ci>RAF</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="Akt">
<variable units="s" public_interface="in" name="time"/>
<variable units="nm" public_interface="in" name="PI3Kstar"/>
<variable units="nm" public_interface="out" name="Akt_PIPP" initial_value="0.0"/>
<variable units="nm" public_interface="in" name="MEKP"/>
<variable units="nm" public_interface="in" name="MEKPP"/>
<variable units="first_order_rate_constant" name="kf27" initial_value="16.9"/>
<variable units="nm" name="k27" initial_value="39.1"/>
<variable units="flux" name="V28" initial_value="17000"/>
<variable units="nm" name="k28" initial_value="9.02"/>
<variable units="second_order_rate_constant" name="kf29" initial_value="507"/>
<variable units="first_order_rate_constant" name="kb29" initial_value="234"/>
<variable units="flux" name="V30" initial_value="20000"/>
<variable units="nm" name="k30" initial_value="80000"/>
<variable units="first_order_rate_constant" name="kf31" initial_value="0.107"/>
<variable units="nm" name="k31" initial_value="4.35"/>
<variable units="flux" name="V32" initial_value="20000"/>
<variable units="nm" name="k32" initial_value="80000"/>
<variable units="first_order_rate_constant" name="kf33" initial_value="0.211"/>
<variable units="nm" name="k33" initial_value="12"/>
<variable units="nm" name="k16" initial_value="2200"/>
<variable units="nm" name="k18" initial_value="60"/>
<variable units="nm" name="P" initial_value="800"/>
<variable units="nm" name="PIP3" initial_value="0"/>
<variable units="nm" name="Akt" initial_value="10"/>
<variable units="nm" name="Akt_PIP3" initial_value="0"/>
<variable units="nm" public_interface="out" name="Akt_PIP" initial_value="0"/>
<variable units="nm" name="PP2A" initial_value="11.4"/>
<variable units="dimensionless" name="one" initial_value="1"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>P</ci>
</apply>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>V28</ci>
<ci>PIP3</ci>
</apply>
<apply>
<plus/>
<ci>k28</ci>
<ci>PIP3</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf27</ci>
<ci>PI3Kstar</ci>
<ci>P</ci>
</apply>
<apply>
<plus/>
<ci>k27</ci>
<ci>P</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>PIP3</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>V28</ci>
<ci>PIP3</ci>
</apply>
<apply>
<plus/>
<ci>k28</ci>
<ci>PIP3</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf27</ci>
<ci>PI3Kstar</ci>
<ci>P</ci>
</apply>
<apply>
<plus/>
<ci>k27</ci>
<ci>P</ci>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>kf29</ci>
<ci>PIP3</ci>
<ci>Akt</ci>
</apply>
<apply>
<times/>
<ci>kb29</ci>
<ci>Akt_PIP3</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Akt</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf29</ci>
<ci>PIP3</ci>
<ci>Akt</ci>
</apply>
<apply>
<times/>
<ci>kb29</ci>
<ci>Akt_PIP3</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Akt_PIP3</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>kf29</ci>
<ci>PIP3</ci>
<ci>Akt</ci>
</apply>
<apply>
<times/>
<ci>kb29</ci>
<ci>Akt_PIP3</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>V30</ci>
<ci>Akt_PIP3</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k30</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>Akt_PIP</ci>
<ci>k32</ci>
</apply>
</apply>
</apply>
<ci>Akt_PIP3</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf31</ci>
<ci>PP2A</ci>
<ci>Akt_PIP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k31</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEKP</ci>
<ci>k16</ci>
</apply>
<apply>
<divide/>
<ci>MEKPP</ci>
<ci>k18</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIPP</ci>
<ci>k33</ci>
</apply>
</apply>
</apply>
<ci>Akt_PIP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Akt_PIP</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>V30</ci>
<ci>Akt_PIP3</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k30</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>Akt_PIP</ci>
<ci>k32</ci>
</apply>
</apply>
</apply>
<ci>Akt_PIP3</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf31</ci>
<ci>PP2A</ci>
<ci>Akt_PIP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k31</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEKP</ci>
<ci>k16</ci>
</apply>
<apply>
<divide/>
<ci>MEKPP</ci>
<ci>k18</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIPP</ci>
<ci>k33</ci>
</apply>
</apply>
</apply>
<ci>Akt_PIP</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>V32</ci>
<ci>Akt_PIP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k32</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>Akt_PIP3</ci>
<ci>k30</ci>
</apply>
</apply>
</apply>
<ci>Akt_PIP</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf33</ci>
<ci>PP2A</ci>
<ci>Akt_PIPP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k33</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEKP</ci>
<ci>k16</ci>
</apply>
<apply>
<divide/>
<ci>MEKPP</ci>
<ci>k18</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIP</ci>
<ci>k31</ci>
</apply>
</apply>
</apply>
<ci>Akt_PIPP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Akt_PIPP</ci>
</apply>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>V32</ci>
<ci>Akt_PIP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k32</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>Akt_PIP3</ci>
<ci>k30</ci>
</apply>
</apply>
</apply>
<ci>Akt_PIP</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf33</ci>
<ci>PP2A</ci>
<ci>Akt_PIPP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k33</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEKP</ci>
<ci>k16</ci>
</apply>
<apply>
<divide/>
<ci>MEKPP</ci>
<ci>k18</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIP</ci>
<ci>k31</ci>
</apply>
</apply>
</apply>
<ci>Akt_PIPP</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="MEK">
<variable units="s" public_interface="in" name="time"/>
<variable units="nm" public_interface="in" name="RAF_star"/>
<variable units="nm" public_interface="out" name="MEKPP" initial_value="0"/>
<variable units="nm" name="PP2A" initial_value="11.4"/>
<variable units="nm" public_interface="out" name="MEKP" initial_value="0"/>
<variable units="nm" name="MEK" initial_value="120"/>
<variable units="nm" public_interface="in" name="Akt_PIP"/>
<variable units="nm" public_interface="in" name="Akt_PIPP"/>
<variable units="first_order_rate_constant" name="kf15" initial_value="3.5"/>
<variable units="nm" name="k15" initial_value="317"/>
<variable units="first_order_rate_constant" name="kf16" initial_value="0.058"/>
<variable units="nm" name="k16" initial_value="2200"/>
<variable units="first_order_rate_constant" name="kf17" initial_value="2.9"/>
<variable units="nm" name="k17" initial_value="317"/>
<variable units="first_order_rate_constant" name="kf18" initial_value="0.058"/>
<variable units="nm" name="k18" initial_value="60"/>
<variable units="nm" name="k31" initial_value="4.35"/>
<variable units="nm" name="k33" initial_value="12"/>
<variable units="dimensionless" name="one" initial_value="1"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MEK</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>kf15</ci>
<ci>RAF_star</ci>
<ci>MEK</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k15</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEKP</ci>
<ci>k17</ci>
</apply>
</apply>
</apply>
<ci>MEK</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf16</ci>
<ci>PP2A</ci>
<ci>MEKP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k16</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEKPP</ci>
<ci>k18</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIP</ci>
<ci>k31</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIPP</ci>
<ci>k33</ci>
</apply>
</apply>
</apply>
<ci>MEKP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MEKP</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>kf15</ci>
<ci>RAF_star</ci>
<ci>MEK</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k15</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEKP</ci>
<ci>k17</ci>
</apply>
</apply>
</apply>
<ci>MEK</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf16</ci>
<ci>PP2A</ci>
<ci>MEKP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k16</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEKPP</ci>
<ci>k18</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIP</ci>
<ci>k31</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIPP</ci>
<ci>k33</ci>
</apply>
</apply>
</apply>
<ci>MEKP</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf17</ci>
<ci>RAF_star</ci>
<ci>MEKP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k17</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEK</ci>
<ci>k15</ci>
</apply>
</apply>
</apply>
<ci>MEKP</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf18</ci>
<ci>PP2A</ci>
<ci>MEKPP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k18</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEKP</ci>
<ci>k16</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIP</ci>
<ci>k31</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIPP</ci>
<ci>k33</ci>
</apply>
</apply>
</apply>
<ci>MEKPP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MEKPP</ci>
</apply>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>kf17</ci>
<ci>RAF_star</ci>
<ci>MEKP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k17</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEK</ci>
<ci>k15</ci>
</apply>
</apply>
</apply>
<ci>MEKP</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf18</ci>
<ci>PP2A</ci>
<ci>MEKPP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k18</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>MEKP</ci>
<ci>k16</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIP</ci>
<ci>k31</ci>
</apply>
<apply>
<divide/>
<ci>Akt_PIPP</ci>
<ci>k33</ci>
</apply>
</apply>
</apply>
<ci>MEKPP</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="ERK">
<variable units="s" public_interface="in" name="time"/>
<variable units="nm" public_interface="in" name="MEKPP"/>
<variable units="nm" name="MKP3" initial_value="2.4"/>
<variable units="nm" name="ERK" initial_value="1000"/>
<variable units="nm" name="ERKP" initial_value="0"/>
<variable units="nm" name="ERKPP" initial_value="0"/>
<variable units="first_order_rate_constant" name="kf19" initial_value="9.5"/>
<variable units="nm" name="k19" initial_value="146000"/>
<variable units="first_order_rate_constant" name="kf20" initial_value="0.3"/>
<variable units="nm" name="k20" initial_value="160"/>
<variable units="first_order_rate_constant" name="kf21" initial_value="16"/>
<variable units="nm" name="k21" initial_value="146000"/>
<variable units="first_order_rate_constant" name="kf22" initial_value="0.27"/>
<variable units="nm" name="k22" initial_value="60"/>
<variable units="dimensionless" name="one" initial_value="1"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>ERK</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>kf19</ci>
<ci>MEKPP</ci>
<ci>ERK</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k19</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>ERKP</ci>
<ci>k21</ci>
</apply>
</apply>
</apply>
<ci>ERK</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf20</ci>
<ci>MKP3</ci>
<ci>ERKP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k20</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>ERKPP</ci>
<ci>k22</ci>
</apply>
</apply>
</apply>
<ci>ERKP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>ERKPP</ci>
</apply>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>kf21</ci>
<ci>MEKPP</ci>
<ci>ERKP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k21</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>ERK</ci>
<ci>k19</ci>
</apply>
</apply>
</apply>
<ci>ERKP</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf22</ci>
<ci>MKP3</ci>
<ci>ERKPP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k22</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>ERKP</ci>
<ci>k20</ci>
</apply>
</apply>
</apply>
<ci>ERKPP</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>ERKP</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>kf19</ci>
<ci>MEKPP</ci>
<ci>ERK</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k19</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>ERKP</ci>
<ci>k21</ci>
</apply>
</apply>
</apply>
<ci>ERK</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf20</ci>
<ci>MKP3</ci>
<ci>ERKP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k20</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>ERKPP</ci>
<ci>k22</ci>
</apply>
</apply>
</apply>
<ci>ERKP</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf21</ci>
<ci>MEKPP</ci>
<ci>ERKP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k21</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>ERK</ci>
<ci>k19</ci>
</apply>
</apply>
</apply>
<ci>ERKP</ci>
</apply>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>kf22</ci>
<ci>MKP3</ci>
<ci>ERKPP</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>k22</ci>
<apply>
<plus/>
<ci>one</ci>
<apply>
<divide/>
<ci>ERKP</ci>
<ci>k20</ci>
</apply>
</apply>
</apply>
<ci>ERKPP</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<connection>
<map_components component_2="environment" component_1="PI3K"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="Akt"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="RAF"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="RasGDPtoRasGTP"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="MEK"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="ERK"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="RasGDPtoRasGTP" component_1="PI3K"/>
<map_variables variable_2="ShGS" variable_1="ShGS"/>
</connection>
<connection>
<map_components component_2="RAF" component_1="RasGDPtoRasGTP"/>
<map_variables variable_2="RasGTP" variable_1="RasGTP"/>
</connection>
<connection>
<map_components component_2="Akt" component_1="RAF"/>
<map_variables variable_2="Akt_PIPP" variable_1="Akt_PIPP"/>
</connection>
<connection>
<map_components component_2="MEK" component_1="Akt"/>
<map_variables variable_2="MEKP" variable_1="MEKP"/>
<map_variables variable_2="MEKPP" variable_1="MEKPP"/>
<map_variables variable_2="Akt_PIP" variable_1="Akt_PIP"/>
<map_variables variable_2="Akt_PIPP" variable_1="Akt_PIPP"/>
</connection>
<connection>
<map_components component_2="MEK" component_1="ERK"/>
<map_variables variable_2="MEKPP" variable_1="MEKPP"/>
</connection>
<connection>
<map_components component_2="MEK" component_1="RAF"/>
<map_variables variable_2="RAF_star" variable_1="RAF_star"/>
</connection>
<connection>
<map_components component_2="Akt" component_1="PI3K"/>
<map_variables variable_2="PI3Kstar" variable_1="PI3Kstar"/>
</connection>
<rdf:RDF>
<rdf:Seq rdf:about="rdf:#4b8aa5ab-0a79-43a4-831d-7d91f6191918">
<rdf:li rdf:resource="rdf:#b3bb192f-a6c2-4524-8870-c9f7e0cb395d"/>
<rdf:li rdf:resource="rdf:#9590e834-5a80-4622-a74d-cd193c7bf5b3"/>
<rdf:li rdf:resource="rdf:#b937e063-b84c-4bd4-9896-0ea82a798a20"/>
<rdf:li rdf:resource="rdf:#bd35959e-d11d-4041-b346-ec769628bf0a"/>
<rdf:li rdf:resource="rdf:#9418e400-0058-4e1a-af77-6fa626f6c85b"/>
<rdf:li rdf:resource="rdf:#afc054f8-64d5-4062-a68e-ec59358088e9"/>
<rdf:li rdf:resource="rdf:#5f1ae78c-b27e-480f-8168-6cae9a4fa714"/>
<rdf:li rdf:resource="rdf:#4380e64e-7800-49db-a47d-5f4209c330b3"/>
<rdf:li rdf:resource="rdf:#7ad23968-7a2c-422e-9563-a1672e5c7829"/>
<rdf:li rdf:resource="rdf:#b926f440-af70-45ea-9e4a-8922602d34a8"/>
<rdf:li rdf:resource="rdf:#a6405285-ae6c-4c66-8ef1-a9aa2dba0bf2"/>
<rdf:li rdf:resource="rdf:#359d9e86-9562-406f-a7f1-7c71942617f6"/>
</rdf:Seq>
<rdf:Description rdf:about="rdf:#c1efcc6c-6f22-48e1-910b-4502f6a68cf9">
<dcterms:W3CDTF>2003-07-15</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="">
<dc:publisher/>
<cmeta:comment rdf:resource="rdf:#01b58e17-0256-4f90-af5e-fe062e53696b"/>
<dcterms:created rdf:resource="rdf:#adbe68a2-4be3-4356-8390-9a1b33410923"/>
<dc:creator rdf:resource="rdf:#0b982b3b-957b-4e0f-ae51-a07d69753957"/>
<cmeta:modification rdf:resource="rdf:#06300c6e-3079-406f-bed8-a105630e7790"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#7ad23968-7a2c-422e-9563-a1672e5c7829">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#dd0b57d1-d231-489f-b26a-bf49197bdd59"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#adbe68a2-4be3-4356-8390-9a1b33410923">
<dcterms:W3CDTF>2007-08-27T00:00:00+00:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#359d9e86-9562-406f-a7f1-7c71942617f6">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#d0a19a37-c244-4e6d-8059-12a3899ad630"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#a1fa1e28-061b-465a-be4b-27f1bca81cbc">
<rdf:type rdf:resource="http://imc.org/vCard/3.0#internet"/>
<rdf:value>m.mccormick@auckland.ac.nz</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#01b58e17-0256-4f90-af5e-fe062e53696b">
<dc:creator rdf:resource="rdf:#fec354de-f07d-4a08-b264-27fef8f02120"/>
<rdf:value>The model now runs in PCEnv to replicate the published results - we think! The only question mark is over how the variables are expressed - as nM in the model and then as %s in the figures. We're not sure why there's this difference.</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#1c74bac1-b157-4719-a651-f270b48ca264">
<dc:creator rdf:resource="rdf:#4b8aa5ab-0a79-43a4-831d-7d91f6191918"/>
<dc:title>A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling</dc:title>
<bqs:volume>373</bqs:volume>
<bqs:first_page>451</bqs:first_page>
<bqs:Journal rdf:resource="rdf:#0d301f2c-f766-48fb-99dc-71d43b3e7e0b"/>
<dcterms:issued rdf:resource="rdf:#c1efcc6c-6f22-48e1-910b-4502f6a68cf9"/>
<bqs:last_page>463</bqs:last_page>
</rdf:Description>
<rdf:Description rdf:about="rdf:#fbd36f2c-1317-4c5d-9fbd-3c852ad23ab6">
<dc:creator rdf:resource="rdf:#1040aaeb-325f-4711-81cb-da8d592223e6"/>
<rdf:value/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#a6405285-ae6c-4c66-8ef1-a9aa2dba0bf2">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#9f417d1d-577a-4d7c-a7fc-499e549bc407"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#9590e834-5a80-4622-a74d-cd193c7bf5b3">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#a41a8346-790a-4c42-a5ae-7850c84d30e6"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#b926f440-af70-45ea-9e4a-8922602d34a8">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#29060d99-83e6-449f-8f70-d7baf3aba53b"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#9418e400-0058-4e1a-af77-6fa626f6c85b">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#2bf5b4f6-9e01-423f-a075-6eb7cccff81c"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#b1c8e269-357d-4aef-8100-e97a3c9f265b">
<bqs:Pubmed_id>12691603</bqs:Pubmed_id>
<bqs:JournalArticle rdf:resource="rdf:#1c74bac1-b157-4719-a651-f270b48ca264"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#b3bb192f-a6c2-4524-8870-c9f7e0cb395d">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#786b5a9d-60af-49ba-b688-ea104d4c9bec"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#58aa6253-dd61-453a-8b51-e4fb7c7cb7e2">
<vCard:Given>Mio</vCard:Given>
<vCard:Family>Ichikawa</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#d0a19a37-c244-4e6d-8059-12a3899ad630">
<vCard:Given>Akihiko</vCard:Given>
<vCard:Family>Konagaya</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#0d301f2c-f766-48fb-99dc-71d43b3e7e0b">
<dc:title>The Biochemical Journal</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#a41a8346-790a-4c42-a5ae-7850c84d30e6">
<vCard:Given>Shuhei</vCard:Given>
<vCard:Family>Kimura</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#b937e063-b84c-4bd4-9896-0ea82a798a20">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#83271030-6d0f-41c4-a9b8-944163c8609b"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#5712261e-d6f8-4028-833d-dc14399f529c">
<dcterms:W3CDTF>2007-10-04T11:06:52+13:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#5f1ae78c-b27e-480f-8168-6cae9a4fa714">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#dc76cc57-9f52-4209-894e-85467cb774aa"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#bd35959e-d11d-4041-b346-ec769628bf0a">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#fa213f0e-1ad1-4880-9fc6-3f2d687a1450"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#786b5a9d-60af-49ba-b688-ea104d4c9bec">
<vCard:Given>Mariko</vCard:Given>
<vCard:Family>Hatakeyama</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#dd0b57d1-d231-489f-b26a-bf49197bdd59">
<vCard:Given>Mihoro</vCard:Given>
<vCard:Family>Saeki</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="#bhalla_model_1999">
<bqs:reference rdf:resource="rdf:#b1c8e269-357d-4aef-8100-e97a3c9f265b"/>
<bqs:reference rdf:parseType="Resource">
<dc:subject rdf:parseType="Resource">
<bqs:subject_type>keyword</bqs:subject_type>
<rdf:value>
<rdf:Bag>
<rdf:li>signal transduction</rdf:li>
<rdf:li>cerebral aneurysm</rdf:li>
</rdf:Bag>
</rdf:value>
</dc:subject>
</bqs:reference>
<cmeta:comment rdf:resource="rdf:#fbd36f2c-1317-4c5d-9fbd-3c852ad23ab6"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#29060d99-83e6-449f-8f70-d7baf3aba53b">
<vCard:Given>Mikako</vCard:Given>
<vCard:Family>Shirouzu</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#afc054f8-64d5-4062-a68e-ec59358088e9">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#58aa6253-dd61-453a-8b51-e4fb7c7cb7e2"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#dc76cc57-9f52-4209-894e-85467cb774aa">
<vCard:Given>Jae-Hoon</vCard:Given>
<vCard:Family>Kim</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#2bf5b4f6-9e01-423f-a075-6eb7cccff81c">
<vCard:Given>Noriko</vCard:Given>
<vCard:Family>Yumoto</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#9f417d1d-577a-4d7c-a7fc-499e549bc407">
<vCard:Given>Shigeyuki</vCard:Given>
<vCard:Family>Yokoyama</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#83271030-6d0f-41c4-a9b8-944163c8609b">
<vCard:Given>Takashi</vCard:Given>
<vCard:Family>Naka</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#eb687547-22e6-44d7-b0b1-04d13f55dfb0">
<vCard:Given>Kazuki</vCard:Given>
<vCard:Family>Saito</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#9ace0219-fc7a-4208-8425-82e8fea8b11b">
<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>The Bioengineering Institute</vCard:Orgunit>
</rdf:Description>
<rdf:Description rdf:about="rdf:#fa213f0e-1ad1-4880-9fc6-3f2d687a1450">
<vCard:Given>Takuji</vCard:Given>
<vCard:Family>Kawasaki</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#944de2c1-85ad-4dd2-86b2-bd6f30ba820e">
<vCard:Given>Catherine</vCard:Given>
<vCard:Family>Lloyd</vCard:Family>
<vCard:Other>May</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#3d848b6a-fb6a-40dd-86d2-27a018cddc24">
<vCard:Given>Matthew</vCard:Given>
<vCard:Family>McCormick</vCard:Family>
<vCard:Other/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#fec354de-f07d-4a08-b264-27fef8f02120">
<vCard:FN>Catherine Lloyd</vCard:FN>
</rdf:Description>
<rdf:Description rdf:about="rdf:#2cff3ad8-e43f-4e00-aa66-20182a34a3c9">
<vCard:N rdf:resource="rdf:#944de2c1-85ad-4dd2-86b2-bd6f30ba820e"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#06300c6e-3079-406f-bed8-a105630e7790">
<dcterms:modified rdf:resource="rdf:#5712261e-d6f8-4028-833d-dc14399f529c"/>
<rdf:value>Checked model in COR. Added a couple of initial values, corrected the unit definitions and also several units in several equations.</rdf:value>
<cmeta:modifier rdf:resource="rdf:#2cff3ad8-e43f-4e00-aa66-20182a34a3c9"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#4380e64e-7800-49db-a47d-5f4209c330b3">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#eb687547-22e6-44d7-b0b1-04d13f55dfb0"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#0b982b3b-957b-4e0f-ae51-a07d69753957">
<vCard:ORG rdf:resource="rdf:#9ace0219-fc7a-4208-8425-82e8fea8b11b"/>
<vCard:EMAIL rdf:resource="rdf:#a1fa1e28-061b-465a-be4b-27f1bca81cbc"/>
<vCard:N rdf:resource="rdf:#3d848b6a-fb6a-40dd-86d2-27a018cddc24"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#1040aaeb-325f-4711-81cb-da8d592223e6">
<vCard:FN/>
</rdf:Description>
</rdf:RDF>
</model>