Rendering of the source text

<?xml version="1.0"?>
<!--
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/
-->
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<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>Auckland Bioengineering Institute, The 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 OpenCell 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>
ABSTRACT: ErbB tyrosine kinase receptors mediate mitogenic signal cascade by binding a variety of ligands and recruiting the different cassettes of adaptor proteins. In the present study, we examined heregulin (HRG)-induced signal transduction of ErbB4 receptor and found that the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway negatively regulated the extracellular signal-regulated kinase (ERK) cascade by phosphorylating Raf-1 on Ser(259). As the time-course kinetics of Akt and ERK activities seemed to be transient and complex, we constructed a mathematical simulation model for HRG-induced ErbB4 receptor signalling to explain the dynamics of the regulation mechanism in this signal transduction cascade. The model reflected well the experimental results observed in HRG-induced ErbB4 cells and in other modes of growth hormone-induced cell signalling that involve Raf-Akt cross-talk. The model suggested that HRG signalling is regulated by protein phosphatase 2A as well as Raf-Akt cross-talk, and protein phosphatase 2A modulates the kinase activity in both the PI3K-Akt and MAPK (mitogen-activated protein kinase) pathways.
</para>

<para>
The original paper reference is cited below:
</para>

<para>
A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling, 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, <emphasis>The Biochemical Journal</emphasis>, 373, 451-463. <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/12691603">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>




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                     <ci>kf25</ci>
                     <ci>R_PI3Kstar</ci>
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                  <apply>
                     <times/>
                     <ci>kb25</ci>
                     <ci>RP</ci>
                     <ci>PI3Kstar</ci>
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               </apply>
               <apply>
                  <divide/>
                  <apply>
                     <times/>
                     <ci>V26</ci>
                     <ci>PI3Kstar</ci>
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                  <apply>
                     <plus/>
                     <ci>k26</ci>
                     <ci>PI3Kstar</ci>
                  </apply>
               </apply>
            </apply>
         </apply>
      </math>
   </component>
   <component name="RasGDPtoRasGTP">
      <variable name="time" public_interface="in" units="s"/>
      <variable name="ShGS" public_interface="in" units="nm"/>
      <variable cmeta:id="RasGDPtoRasGTP_RasGTP" initial_value="0" name="RasGTP" public_interface="out" units="nm"/>
      <variable initial_value="0.222" name="kf11" units="first_order_rate_constant"/>
      <variable initial_value="0.181" name="k11" units="nm"/>
      <variable initial_value="0.289" name="V12" units="flux"/>
      <variable initial_value="0.0571" name="k12" units="nm"/>
      <variable cmeta:id="RasGDPtoRasGTP_RasGDP" initial_value="120" name="RasGDP" units="nm"/>
      <math xmlns="http://www.w3.org/1998/Math/MathML">
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>RasGDP</ci>
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            <apply>
               <plus/>
               <apply>
                  <minus/>
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                     <divide/>
                     <apply>
                        <times/>
                        <ci>kf11</ci>
                        <ci>ShGS</ci>
                        <ci>RasGDP</ci>
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                     <apply>
                        <plus/>
                        <ci>k11</ci>
                        <ci>RasGDP</ci>
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               <apply>
                  <divide/>
                  <apply>
                     <times/>
                     <ci>V12</ci>
                     <ci>RasGTP</ci>
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                  <apply>
                     <plus/>
                     <ci>k12</ci>
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            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>RasGTP</ci>
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            <apply>
               <minus/>
               <apply>
                  <divide/>
                  <apply>
                     <times/>
                     <ci>kf11</ci>
                     <ci>ShGS</ci>
                     <ci>RasGDP</ci>
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                  <apply>
                     <plus/>
                     <ci>k11</ci>
                     <ci>RasGDP</ci>
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               </apply>
               <apply>
                  <divide/>
                  <apply>
                     <times/>
                     <ci>V12</ci>
                     <ci>RasGTP</ci>
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                  <apply>
                     <plus/>
                     <ci>k12</ci>
                     <ci>RasGTP</ci>
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               </apply>
            </apply>
         </apply>
      </math>
   </component>
   <component name="RAF">
      <variable name="time" public_interface="in" units="s"/>
      <variable name="RasGTP" public_interface="in" units="nm"/>
      <variable name="Akt_PIPP" public_interface="in" units="nm"/>
      <variable cmeta:id="RAF_RAF_star" initial_value="100" name="RAF_star" public_interface="out" units="nm"/>
      <variable initial_value="1.53" name="kf13" units="first_order_rate_constant"/>
      <variable initial_value="11.7" name="k13" units="nm"/>
      <variable initial_value="0.00673" name="kf14" units="first_order_rate_constant"/>
      <variable initial_value="8.07" name="k14" units="nm"/>
      <variable initial_value="7" name="E" units="nm"/>
      <variable cmeta:id="RAF_RAF" initial_value="0" name="RAF" units="nm"/>
      <math xmlns="http://www.w3.org/1998/Math/MathML">
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>RAF</ci>
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            <apply>
               <minus/>
               <apply>
                  <divide/>
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                     <times/>
                     <ci>kf14</ci>
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                        <plus/>
                        <ci>Akt_PIPP</ci>
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                  <divide/>
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                     <times/>
                     <ci>kf13</ci>
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                     <plus/>
                     <ci>k13</ci>
                     <ci>RAF</ci>
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         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
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               <ci>RAF_star</ci>
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            <apply>
               <plus/>
               <apply>
                  <minus/>
                  <apply>
                     <divide/>
                     <apply>
                        <times/>
                        <ci>kf14</ci>
                        <apply>
                           <plus/>
                           <ci>Akt_PIPP</ci>
                           <ci>E</ci>
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                     <apply>
                        <plus/>
                        <ci>k14</ci>
                        <ci>RAF_star</ci>
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                  </apply>
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               <apply>
                  <divide/>
                  <apply>
                     <times/>
                     <ci>kf13</ci>
                     <ci>RasGTP</ci>
                     <ci>RAF</ci>
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                  <apply>
                     <plus/>
                     <ci>k13</ci>
                     <ci>RAF</ci>
                  </apply>
               </apply>
            </apply>
         </apply>
      </math>
   </component>
   <component name="Akt">
      <variable name="time" public_interface="in" units="s"/>
      <variable name="PI3Kstar" public_interface="in" units="nm"/>
      <variable cmeta:id="Akt_Akt_PIPP" initial_value="0.0" name="Akt_PIPP" public_interface="out" units="nm"/>
      <variable name="MEKP" public_interface="in" units="nm"/>
      <variable name="MEKPP" public_interface="in" units="nm"/>
      <variable initial_value="16.9" name="kf27" units="first_order_rate_constant"/>
      <variable initial_value="39.1" name="k27" units="nm"/>
      <variable initial_value="17000" name="V28" units="flux"/>
      <variable initial_value="9.02" name="k28" units="nm"/>
      <variable initial_value="507" name="kf29" units="second_order_rate_constant"/>
      <variable initial_value="234" name="kb29" units="first_order_rate_constant"/>
      <variable initial_value="20000" name="V30" units="flux"/>
      <variable initial_value="80000" name="k30" units="nm"/>
      <variable initial_value="0.107" name="kf31" units="first_order_rate_constant"/>
      <variable initial_value="4.35" name="k31" units="nm"/>
      <variable initial_value="20000" name="V32" units="flux"/>
      <variable initial_value="80000" name="k32" units="nm"/>
      <variable initial_value="0.211" name="kf33" units="first_order_rate_constant"/>
      <variable initial_value="12" name="k33" units="nm"/>
      <variable initial_value="2200" name="k16" units="nm"/>
      <variable initial_value="60" name="k18" units="nm"/>
      <variable initial_value="800" name="P" units="nm"/>
      <variable cmeta:id="Akt_PIP3" initial_value="0" name="PIP3" units="nm"/>
      <variable cmeta:id="Akt_Akt" initial_value="10" name="Akt" units="nm"/>
      <variable cmeta:id="Akt_Akt_PIP3" initial_value="0" name="Akt_PIP3" units="nm"/>
      <variable cmeta:id="Akt_Akt_PIP" initial_value="0" name="Akt_PIP" public_interface="out" units="nm"/>
      <variable initial_value="11.4" name="PP2A" units="nm"/>
      <variable initial_value="1" name="one" units="dimensionless"/>
      <math xmlns="http://www.w3.org/1998/Math/MathML">
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
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               <ci>P</ci>
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            <apply>
               <minus/>
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                  <divide/>
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                     <times/>
                     <ci>V28</ci>
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                     <plus/>
                     <ci>k28</ci>
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                  <divide/>
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                     <times/>
                     <ci>kf27</ci>
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                     <ci>k27</ci>
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            <eq/>
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               <diff/>
               <bvar>
                  <ci>time</ci>
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               <ci>PIP3</ci>
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               <minus/>
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                  <plus/>
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                     <minus/>
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                        <divide/>
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                           <times/>
                           <ci>V28</ci>
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                           <plus/>
                           <ci>k28</ci>
                           <ci>PIP3</ci>
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                     <divide/>
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                        <times/>
                        <ci>kf27</ci>
                        <ci>PI3Kstar</ci>
                        <ci>P</ci>
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                        <plus/>
                        <ci>k27</ci>
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                     <times/>
                     <ci>kf29</ci>
                     <ci>PIP3</ci>
                     <ci>Akt</ci>
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                  <apply>
                     <times/>
                     <ci>kb29</ci>
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            <eq/>
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               <diff/>
               <bvar>
                  <ci>time</ci>
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               <ci>Akt</ci>
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                  <minus/>
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                     <times/>
                     <ci>kf29</ci>
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                     <ci>Akt</ci>
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                     <times/>
                     <ci>kb29</ci>
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         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
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               <ci>Akt_PIP3</ci>
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               <plus/>
               <apply>
                  <minus/>
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                     <minus/>
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                        <times/>
                        <ci>kf29</ci>
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                        <ci>Akt</ci>
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                        <times/>
                        <ci>kb29</ci>
                        <ci>Akt_PIP3</ci>
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                        <times/>
                        <ci>V30</ci>
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                        <plus/>
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                           <times/>
                           <ci>k30</ci>
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                              <ci>one</ci>
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                                 <divide/>
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                     <times/>
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                        <times/>
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                           <plus/>
                           <ci>one</ci>
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                              <divide/>
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                              <divide/>
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                              <ci>k33</ci>
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               <diff/>
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                              <ci>k30</ci>
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                           <ci>kf31</ci>
                           <ci>PP2A</ci>
                           <ci>Akt_PIP</ci>
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                                 <ci>one</ci>
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                                    <divide/>
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                                    <divide/>
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                                    <ci>k18</ci>
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                                 <apply>
                                    <divide/>
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                                    <ci>k33</ci>
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                        </apply>
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                  <apply>
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                        <times/>
                        <ci>V32</ci>
                        <ci>Akt_PIP</ci>
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                     <apply>
                        <plus/>
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                           <times/>
                           <ci>k32</ci>
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                              <plus/>
                              <ci>one</ci>
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                                 <divide/>
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                                 <ci>k30</ci>
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                        <ci>Akt_PIP</ci>
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               <apply>
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                     <times/>
                     <ci>kf33</ci>
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                     <ci>Akt_PIPP</ci>
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                     <plus/>
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                        <times/>
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                           <plus/>
                           <ci>one</ci>
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                              <divide/>
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                        <times/>
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                           <ci>one</ci>
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                     <ci>Akt_PIPP</ci>
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            </apply>
         </apply>
      </math>
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      <variable name="RAF_star" public_interface="in" units="nm"/>
      <variable cmeta:id="MEK_MEKPP" initial_value="0" name="MEKPP" public_interface="out" units="nm"/>
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      <variable cmeta:id="MEK_MEK" initial_value="120" name="MEK" units="nm"/>
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      <variable name="Akt_PIPP" public_interface="in" units="nm"/>
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      <variable initial_value="0.058" name="kf16" units="first_order_rate_constant"/>
      <variable initial_value="2200" name="k16" units="nm"/>
      <variable initial_value="2.9" name="kf17" units="first_order_rate_constant"/>
      <variable initial_value="317" name="k17" units="nm"/>
      <variable initial_value="0.058" name="kf18" units="first_order_rate_constant"/>
      <variable initial_value="60" name="k18" units="nm"/>
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      <variable initial_value="12" name="k33" units="nm"/>
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                  <ci>time</ci>
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                  <minus/>
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                        <times/>
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                        <times/>
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                           <ci>one</ci>
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               <plus/>
               <apply>
                  <minus/>
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                     <minus/>
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                        <divide/>
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                           <times/>
                           <ci>kf15</ci>
                           <ci>RAF_star</ci>
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                           <plus/>
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                              <times/>
                              <ci>k15</ci>
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                                 <plus/>
                                 <ci>one</ci>
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                                    <divide/>
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                           <times/>
                           <ci>kf16</ci>
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                           <ci>MEKP</ci>
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                           <plus/>
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                              <times/>
                              <ci>k16</ci>
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                                 <plus/>
                                 <ci>one</ci>
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                                    <divide/>
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                                    <divide/>
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                                    <divide/>
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                        <times/>
                        <ci>kf17</ci>
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rdf:nodeID="n1"/></reference><simulation xmlns="http://www.cellml.org/metadata/simulation/1.0#"><rdf:Description rdf:nodeID="n4"/></simulation></rdf:Description><rdf:Description rdf:nodeID="n5"><pointDensity xmlns="http://www.cellml.org/metadata/simulation/1.0#nonstandard-" xml:lang="en">1000000</pointDensity><endingValue xmlns="http://www.cellml.org/metadata/simulation/1.0#" xml:lang="en">500</endingValue></rdf:Description><rdf:Description rdf:nodeID="n4"><boundIntervals xmlns="http://www.cellml.org/metadata/simulation/1.0#"><rdf:Description rdf:nodeID="n6"/></boundIntervals></rdf:Description><rdf:Description rdf:nodeID="n3"><rdf:type><rdf:Description rdf:about="http://www.w3.org/1999/02/22-rdf-syntax-ns#Bag"/></rdf:type><rdf:_2 xml:lang="en">cerebral aneurysm</rdf:_2><rdf:_1 xml:lang="en">signal transduction</rdf:_1></rdf:Description><rdf:Description rdf:about="rdf:#b937e063-b84c-4bd4-9896-0ea82a798a20"><rdf:type><rdf:Description rdf:about="http://www.cellml.org/bqs/1.0#Person"/></rdf:type><N xmlns="http://www.w3.org/2001/vcard-rdf/3.0#"><rdf:Description rdf:about="rdf:#83271030-6d0f-41c4-a9b8-944163c8609b"/></N></rdf:Description><rdf:Description rdf:about="rdf:#06300c6e-3079-406f-bed8-a105630e7790"><rdf:value xml:lang="en">Checked model in COR.  Added a couple of initial values, corrected the unit definitions and also several units in several equations.</rdf:value><modified xmlns="http://purl.org/dc/terms/"><rdf:Description rdf:about="rdf:#5712261e-d6f8-4028-833d-dc14399f529c"/></modified><cmeta:modifier><rdf:Description rdf:about="rdf:#2cff3ad8-e43f-4e00-aa66-20182a34a3c9"/></cmeta:modifier></rdf:Description><rdf:Description rdf:about="rdf:#c1efcc6c-6f22-48e1-910b-4502f6a68cf9"><W3CDTF xmlns="http://purl.org/dc/terms/" xml:lang="en">2003-07-15</W3CDTF></rdf:Description><rdf:Description rdf:about="rdf:#eb687547-22e6-44d7-b0b1-04d13f55dfb0"><Family xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Saito</Family><Given xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Kazuki</Given></rdf:Description><rdf:Description rdf:about="rdf:#01b58e17-0256-4f90-af5e-fe062e53696b"><creator xmlns="http://purl.org/dc/elements/1.1/"><rdf:Description rdf:about="rdf:#fec354de-f07d-4a08-b264-27fef8f02120"/></creator><rdf:value xml:lang="en">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:#2bf5b4f6-9e01-423f-a075-6eb7cccff81c"><Family xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Yumoto</Family><Given xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Noriko</Given></rdf:Description><rdf:Description rdf:nodeID="n6"><rdf:first><rdf:Description rdf:nodeID="n5"/></rdf:first><rdf:rest><rdf:Description rdf:about="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/></rdf:rest></rdf:Description></rdf:RDF></model>