<?xml version="1.0"?>
<model 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:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" name="fujita_2010" cmeta:id="fujita_2010" xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>Decoupling of receptor and downstream signals in the Akt pathway by its low-pass filter characteristics</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This CellML represents the EGFR-inhibited Akt Pathway model from the original publication (EGF has been set to 30 and the inhibitor to 15). The model runs in both COR and OpenCell 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: In cellular signal transduction, the information in an external stimulus is encoded in temporal patterns in the activities of signaling molecules; for example, pulses of a stimulus may produce an increasing response or may produce pulsatile responses in the signaling molecules. Here, we show how the Akt pathway, which is involved in cell growth, specifically transmits temporal information contained in upstream signals to downstream effectors. We modeled the epidermal growth factor (EGF)-dependent Akt pathway in PC12 cells on the basis of experimental results. We obtained counterintuitive results indicating that the sizes of the peak amplitudes of receptor and downstream effector phosphorylation were decoupled; weak, sustained EGF receptor (EGFR) phosphorylation, rather than strong, transient phosphorylation, strongly induced phosphorylation of the ribosomal protein S6, a molecule downstream of Akt. Using frequency response analysis, we found that a three-component Akt pathway exhibited the property of a low-pass filter and that this property could explain decoupling of the peak amplitudes of receptor phosphorylation and that of downstream effectors. Furthermore, we found that lapatinib, an EGFR inhibitor used as an anticancer drug, converted strong, transient Akt phosphorylation into weak, sustained Akt phosphorylation, and, because of the low-pass filter characteristics of the Akt pathway, this led to stronger S6 phosphorylation than occurred in the absence of the inhibitor. Thus, an EGFR inhibitor can potentially act as a downstream activator of some effectors.
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
</objectinfo>
<imagedata fileref="fujita_2010c.png"/>
</imageobject>
</mediaobject>
<caption>Schematic diagram of the simple simulation model of the EGFR-inhibited Akt pathway.</caption>
</informalfigure>
<para>
The original paper reference is cited below:
</para>
<para>
Decoupling of receptor and downstream signals in the Akt pathway by its low-pass filter characteristics, Fujita KA, Toyoshima Y, Uda S, Ozaki Y, Kubota H, and Kuroda S, 2009, <emphasis>Science Signaling</emphasis>, 3, issue 132. <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/20664065">PubMed ID: 20664065</ulink></para>
</sect1>
</article>
</documentation>
<units name="first_order_rate_constant">
<unit exponent="-1" units="second"/>
</units>
<component name="environment">
<variable name="time" public_interface="out" units="second"/>
</component>
<component name="EGF">
<variable initial_value="30.0" name="EGF" public_interface="out" units="dimensionless"/>
</component>
<component name="inhibitor">
<variable initial_value="15.0" name="inhibitor" public_interface="out" units="dimensionless"/>
</component>
<component name="pro_EGFR">
<variable initial_value="6.81902e-4" name="pro_EGFR" public_interface="out" units="dimensionless"/>
</component>
<component name="EGFR">
<variable initial_value="68190.000000002" name="EGFR" public_interface="out" units="dimensionless"/>
<variable name="EGF_EGFR" public_interface="in" units="dimensionless"/>
<variable name="EGF" public_interface="in" units="dimensionless"/>
<variable name="pro_EGFR" public_interface="in" units="dimensionless"/>
<variable name="inhibitor" public_interface="in" units="dimensionless"/>
<variable name="EGFR_i" public_interface="in" units="dimensionless"/>
<variable name="EGF_binding_kb" public_interface="in" units="first_order_rate_constant"/>
<variable name="EGF_binding_kf" public_interface="in" units="first_order_rate_constant"/>
<variable name="inhibitor_binding_kb" public_interface="in" units="first_order_rate_constant"/>
<variable name="inhibitor_binding_kf" public_interface="in" units="first_order_rate_constant"/>
<variable name="EGFR_turnover" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> EGFR </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> EGF_binding_kb </ci>
<ci> EGF_EGFR </ci>
</apply>
<apply>
<times/>
<ci> inhibitor_binding_kb </ci>
<ci> EGFR_i </ci>
</apply>
<apply>
<times/>
<ci> EGFR_turnover </ci>
<apply>
<minus/>
<ci> pro_EGFR </ci>
<ci> EGFR </ci>
</apply>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> EGF_binding_kf </ci>
<ci> EGF </ci>
<ci> EGFR </ci>
</apply>
<apply>
<times/>
<ci> inhibitor_binding_kf </ci>
<ci> inhibitor </ci>
<ci> EGFR </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="EGF_EGFR">
<variable initial_value="0.0" name="EGF_EGFR" public_interface="out" units="dimensionless"/>
<variable name="EGFR" public_interface="in" units="dimensionless"/>
<variable name="EGF" public_interface="in" units="dimensionless"/>
<variable name="inhibitor" public_interface="in" units="dimensionless"/>
<variable name="EGF_EGFR_i" public_interface="in" units="dimensionless"/>
<variable name="EGF_binding_kb" public_interface="in" units="first_order_rate_constant"/>
<variable name="EGF_binding_kf" public_interface="in" units="first_order_rate_constant"/>
<variable name="inhibitor_binding_kb" public_interface="in" units="first_order_rate_constant"/>
<variable name="inhibitor_binding_kf" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_EGFR_phosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> EGF_EGFR </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> EGF_binding_kf </ci>
<ci> EGF </ci>
<ci> EGFR </ci>
</apply>
<apply>
<times/>
<ci> inhibitor_binding_kb </ci>
<ci> EGF_EGFR_i </ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> EGF_binding_kb </ci>
<ci> EGF_EGFR </ci>
</apply>
<apply>
<times/>
<ci> inhibitor_binding_kf </ci>
<ci> inhibitor </ci>
<ci> EGF_EGFR </ci>
</apply>
<apply>
<times/>
<ci> k1_EGFR_phosphorylation </ci>
<ci> EGF_EGFR </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="EGFR_i">
<variable initial_value="0.0" name="EGFR_i" public_interface="out" units="dimensionless"/>
<variable name="EGF_EGFR_i" public_interface="in" units="dimensionless"/>
<variable name="EGF" public_interface="in" units="dimensionless"/>
<variable name="EGFR" public_interface="in" units="dimensionless"/>
<variable name="inhibitor" public_interface="in" units="dimensionless"/>
<variable name="EGF_binding_kb" public_interface="in" units="first_order_rate_constant"/>
<variable name="EGF_binding_kf" public_interface="in" units="first_order_rate_constant"/>
<variable name="inhibitor_binding_kb" public_interface="in" units="first_order_rate_constant"/>
<variable name="inhibitor_binding_kf" public_interface="in" units="first_order_rate_constant"/>
<variable name="EGFR_turnover" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> EGFR_i </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> EGF_binding_kb </ci>
<ci> EGF_EGFR_i </ci>
</apply>
<apply>
<times/>
<ci> inhibitor_binding_kf </ci>
<ci> inhibitor </ci>
<ci> EGFR </ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> EGF_binding_kf </ci>
<ci> EGF </ci>
<ci> EGFR_i </ci>
</apply>
<apply>
<times/>
<ci> inhibitor_binding_kb </ci>
<ci> EGFR_i </ci>
</apply>
<apply>
<times/>
<ci> EGFR_turnover </ci>
<ci> EGFR_i </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="EGF_EGFR_i">
<variable initial_value="0.0" name="EGF_EGFR_i" public_interface="out" units="dimensionless"/>
<variable name="EGFR_i" public_interface="in" units="dimensionless"/>
<variable name="EGF" public_interface="in" units="dimensionless"/>
<variable name="EGF_EGFR" public_interface="in" units="dimensionless"/>
<variable name="inhibitor" public_interface="in" units="dimensionless"/>
<variable name="EGF_binding_kb" public_interface="in" units="first_order_rate_constant"/>
<variable name="EGF_binding_kf" public_interface="in" units="first_order_rate_constant"/>
<variable name="inhibitor_binding_kb" public_interface="in" units="first_order_rate_constant"/>
<variable name="inhibitor_binding_kf" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> EGF_EGFR_i </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> EGF_binding_kf </ci>
<ci> EGF </ci>
<ci> EGFR_i </ci>
</apply>
<apply>
<times/>
<ci> inhibitor_binding_kf </ci>
<ci> inhibitor </ci>
<ci> EGF_EGFR </ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> EGF_binding_kb </ci>
<ci> EGF_EGFR_i </ci>
</apply>
<apply>
<times/>
<ci> inhibitor_binding_kb </ci>
<ci> EGF_EGFR_i </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="pEGFR">
<variable initial_value="0.0" name="pEGFR" public_interface="out" units="dimensionless"/>
<variable name="EGF_EGFR" public_interface="in" units="dimensionless"/>
<variable name="pEGFR_Akt" public_interface="in" units="dimensionless"/>
<variable name="Akt" public_interface="in" units="dimensionless"/>
<variable name="k1_pEGFR_degradation" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_Akt_phosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_EGFR_phosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_pEGFR_Akt" public_interface="in" units="first_order_rate_constant"/>
<variable name="k2_pEGFR_Akt" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> pEGFR </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> k1_EGFR_phosphorylation </ci>
<ci> EGF_EGFR </ci>
</apply>
<apply>
<times/>
<ci> k1_Akt_phosphorylation </ci>
<ci> pEGFR_Akt </ci>
</apply>
<apply>
<times/>
<ci> k2_pEGFR_Akt </ci>
<ci> pEGFR_Akt </ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> k1_pEGFR_degradation </ci>
<ci> pEGFR </ci>
</apply>
<apply>
<times/>
<ci> k1_pEGFR_Akt </ci>
<ci> pEGFR </ci>
<ci> Akt </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="pEGFR_Akt">
<variable initial_value="0.0" name="pEGFR_Akt" public_interface="out" units="dimensionless"/>
<variable name="pEGFR" public_interface="in" units="dimensionless"/>
<variable name="Akt" public_interface="in" units="dimensionless"/>
<variable name="k1_Akt_phosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_pEGFR_Akt" public_interface="in" units="first_order_rate_constant"/>
<variable name="k2_pEGFR_Akt" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> pEGFR_Akt </ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> k1_pEGFR_Akt </ci>
<ci> pEGFR </ci>
<ci> Akt </ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> k2_pEGFR_Akt </ci>
<ci> pEGFR_Akt </ci>
</apply>
<apply>
<times/>
<ci> k1_Akt_phosphorylation </ci>
<ci> pEGFR_Akt </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="Akt">
<variable initial_value="4.33090e-2" name="Akt" public_interface="out" units="dimensionless"/>
<variable name="pEGFR" public_interface="in" units="dimensionless"/>
<variable name="pEGFR_Akt" public_interface="in" units="dimensionless"/>
<variable name="pAkt" public_interface="in" units="dimensionless"/>
<variable name="k1_pAkt_dephosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_pEGFR_Akt" public_interface="in" units="first_order_rate_constant"/>
<variable name="k2_pEGFR_Akt" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> Akt </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> k2_pEGFR_Akt </ci>
<ci> pEGFR_Akt </ci>
</apply>
<apply>
<times/>
<ci> k1_pAkt_dephosphorylation </ci>
<ci> pAkt </ci>
</apply>
</apply>
<apply>
<times/>
<ci> k1_pEGFR_Akt </ci>
<ci> pEGFR </ci>
<ci> Akt </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="pAkt">
<variable initial_value="0.0" name="pAkt" public_interface="out" units="dimensionless"/>
<variable name="S6" public_interface="in" units="dimensionless"/>
<variable name="pEGFR_Akt" public_interface="in" units="dimensionless"/>
<variable name="pAkt_S6" public_interface="in" units="dimensionless"/>
<variable name="k1_Akt_phosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_pAkt_S6" public_interface="in" units="first_order_rate_constant"/>
<variable name="k2_pAkt_S6" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_S6_phosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_pAkt_dephosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> pAkt </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> k1_Akt_phosphorylation </ci>
<ci> pEGFR_Akt </ci>
</apply>
<apply>
<times/>
<ci> k2_pAkt_S6 </ci>
<ci> pAkt_S6 </ci>
</apply>
<apply>
<times/>
<ci> k1_S6_phosphorylation </ci>
<ci> pAkt_S6 </ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> k1_pAkt_dephosphorylation </ci>
<ci> pAkt </ci>
</apply>
<apply>
<times/>
<ci> k1_pAkt_S6 </ci>
<ci> pAkt </ci>
<ci> S6 </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="pAkt_S6">
<variable initial_value="0.0" name="pAkt_S6" public_interface="out" units="dimensionless"/>
<variable name="S6" public_interface="in" units="dimensionless"/>
<variable name="pAkt" public_interface="in" units="dimensionless"/>
<variable name="k1_pAkt_S6" public_interface="in" units="first_order_rate_constant"/>
<variable name="k2_pAkt_S6" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_S6_phosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> pAkt_S6 </ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> k1_pAkt_S6 </ci>
<ci> pAkt </ci>
<ci> S6 </ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> k2_pAkt_S6 </ci>
<ci> pAkt_S6 </ci>
</apply>
<apply>
<times/>
<ci> k1_S6_phosphorylation </ci>
<ci> pAkt_S6 </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="S6">
<variable initial_value="3.54317e0" name="S6" public_interface="out" units="dimensionless"/>
<variable name="pAkt_S6" public_interface="in" units="dimensionless"/>
<variable name="pS6" public_interface="in" units="dimensionless"/>
<variable name="pAkt" public_interface="in" units="dimensionless"/>
<variable name="k1_pAkt_S6" public_interface="in" units="first_order_rate_constant"/>
<variable name="k2_pAkt_S6" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_pS6_dephosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> S6 </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> k2_pAkt_S6 </ci>
<ci> pAkt_S6 </ci>
</apply>
<apply>
<times/>
<ci> k1_pS6_dephosphorylation </ci>
<ci> pS6 </ci>
</apply>
</apply>
<apply>
<times/>
<ci> k1_pAkt_S6 </ci>
<ci> pAkt </ci>
<ci> S6 </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="pS6">
<variable initial_value="0.0" name="pS6" public_interface="out" units="dimensionless"/>
<variable name="pAkt_S6" public_interface="in" units="dimensionless"/>
<variable name="k1_S6_phosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="k1_pS6_dephosphorylation" public_interface="in" units="first_order_rate_constant"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> pS6 </ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> k1_S6_phosphorylation </ci>
<ci> pAkt_S6 </ci>
</apply>
<apply>
<times/>
<ci> k1_pS6_dephosphorylation </ci>
<ci> pS6 </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="pEGFR_total">
<variable name="pEGFR_total" units="dimensionless"/>
<variable name="pEGFR_scalefactor" units="dimensionless" initial_value="1.81735e-4"/>
<variable name="pEGFR" public_interface="in" units="dimensionless"/>
<variable name="pEGFR_Akt" public_interface="in" units="dimensionless"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> pEGFR_total </ci>
<apply>
<times/>
<apply>
<plus/>
<ci> pEGFR </ci>
<ci> pEGFR_Akt </ci>
</apply>
<ci> pEGFR_scalefactor </ci>
</apply>
</apply>
</math>
</component>
<component name="pAkt_total">
<variable name="pAkt_total" units="dimensionless"/>
<variable name="pAkt_scalefactor" units="dimensionless" initial_value="6.00588e1"/>
<variable name="pAkt" public_interface="in" units="dimensionless"/>
<variable name="pAkt_S6" public_interface="in" units="dimensionless"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> pAkt_total </ci>
<apply>
<times/>
<apply>
<plus/>
<ci> pAkt </ci>
<ci> pAkt_S6 </ci>
</apply>
<ci> pAkt_scalefactor </ci>
</apply>
</apply>
</math>
</component>
<component name="pS6_total">
<variable name="pS6_total" units="dimensionless"/>
<variable name="pS6_scalefactor" units="dimensionless" initial_value="4.98862e4"/>
<variable name="pS6" public_interface="in" units="dimensionless"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> pS6_total </ci>
<apply>
<times/>
<ci> pS6 </ci>
<ci> pS6_scalefactor </ci>
</apply>
</apply>
</math>
</component>
<component name="model_parameters">
<variable name="EGF_binding_kb" public_interface="out" units="first_order_rate_constant" initial_value="4.07490e-2"/>
<variable name="EGF_binding_kf" public_interface="out" units="first_order_rate_constant" initial_value="6.73816e-3"/>
<variable name="inhibitor_binding_kb" public_interface="out" units="first_order_rate_constant" initial_value="5.25097e-5"/>
<variable name="inhibitor_binding_kf" public_interface="out" units="first_order_rate_constant" initial_value="2.434663e-5"/>
<variable name="EGFR_turnover" public_interface="out" units="first_order_rate_constant" initial_value="1.06386129269658e-4"/>
<variable name="k1_S6_phosphorylation" public_interface="out" units="first_order_rate_constant" initial_value="1.21498e-3"/>
<variable name="k1_pS6_dephosphorylation" public_interface="out" units="first_order_rate_constant" initial_value="1.13102e-3"/>
<variable name="k1_pAkt_S6" public_interface="out" units="first_order_rate_constant" initial_value="2.10189e-6"/>
<variable name="k2_pAkt_S6" public_interface="out" units="first_order_rate_constant" initial_value="5.17940e-15"/>
<variable name="k1_Akt_phosphorylation" public_interface="out" units="first_order_rate_constant" initial_value="3.05684e-2"/>
<variable name="k1_pAkt_dephosphorylation" public_interface="out" units="first_order_rate_constant" initial_value="3.27962e-2"/>
<variable name="k1_pEGFR_Akt" public_interface="out" units="first_order_rate_constant" initial_value="1.55430e-5"/>
<variable name="k2_pEGFR_Akt" public_interface="out" units="first_order_rate_constant" initial_value="5.17473e-3"/>
<variable name="k1_pEGFR_degradation" public_interface="out" units="first_order_rate_constant" initial_value="9.97194e-2"/>
<variable name="k1_EGFR_phosphorylation" public_interface="out" units="first_order_rate_constant" initial_value="1.92391e-2"/>
</component>
<connection>
<map_components component_1="EGFR" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="EGF_EGFR" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="EGFR_i" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="EGF_EGFR_i" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="pEGFR" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="pEGFR_Akt" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Akt" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="pAkt" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="pAkt_S6" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="S6" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="pS6" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="EGFR" component_2="EGF_EGFR"/>
<map_variables variable_1="EGF_EGFR" variable_2="EGF_EGFR"/>
<map_variables variable_1="EGFR" variable_2="EGFR"/>
</connection>
<connection>
<map_components component_1="EGFR" component_2="EGFR_i"/>
<map_variables variable_1="EGFR_i" variable_2="EGFR_i"/>
<map_variables variable_1="EGFR" variable_2="EGFR"/>
</connection>
<connection>
<map_components component_1="EGFR" component_2="EGF"/>
<map_variables variable_1="EGF" variable_2="EGF"/>
</connection>
<connection>
<map_components component_1="EGFR" component_2="inhibitor"/>
<map_variables variable_1="inhibitor" variable_2="inhibitor"/>
</connection>
<connection>
<map_components component_1="EGFR" component_2="pro_EGFR"/>
<map_variables variable_1="pro_EGFR" variable_2="pro_EGFR"/>
</connection>
<connection>
<map_components component_1="EGFR" component_2="model_parameters"/>
<map_variables variable_1="EGF_binding_kf" variable_2="EGF_binding_kf"/>
<map_variables variable_1="EGF_binding_kb" variable_2="EGF_binding_kb"/>
<map_variables variable_1="inhibitor_binding_kf" variable_2="inhibitor_binding_kf"/>
<map_variables variable_1="inhibitor_binding_kb" variable_2="inhibitor_binding_kb"/>
<map_variables variable_1="EGFR_turnover" variable_2="EGFR_turnover"/>
</connection>
<connection>
<map_components component_1="EGF_EGFR" component_2="EGF"/>
<map_variables variable_1="EGF" variable_2="EGF"/>
</connection>
<connection>
<map_components component_1="EGF_EGFR" component_2="EGF_EGFR_i"/>
<map_variables variable_1="EGF_EGFR_i" variable_2="EGF_EGFR_i"/>
<map_variables variable_1="EGF_EGFR" variable_2="EGF_EGFR"/>
</connection>
<connection>
<map_components component_1="EGF_EGFR" component_2="inhibitor"/>
<map_variables variable_1="inhibitor" variable_2="inhibitor"/>
</connection>
<connection>
<map_components component_1="EGF_EGFR" component_2="model_parameters"/>
<map_variables variable_1="EGF_binding_kf" variable_2="EGF_binding_kf"/>
<map_variables variable_1="EGF_binding_kb" variable_2="EGF_binding_kb"/>
<map_variables variable_1="inhibitor_binding_kf" variable_2="inhibitor_binding_kf"/>
<map_variables variable_1="inhibitor_binding_kb" variable_2="inhibitor_binding_kb"/>
<map_variables variable_1="k1_EGFR_phosphorylation" variable_2="k1_EGFR_phosphorylation"/>
</connection>
<connection>
<map_components component_1="EGFR_i" component_2="EGF_EGFR_i"/>
<map_variables variable_1="EGF_EGFR_i" variable_2="EGF_EGFR_i"/>
<map_variables variable_1="EGFR_i" variable_2="EGFR_i"/>
</connection>
<connection>
<map_components component_1="EGFR_i" component_2="EGF"/>
<map_variables variable_1="EGF" variable_2="EGF"/>
</connection>
<connection>
<map_components component_1="EGFR_i" component_2="inhibitor"/>
<map_variables variable_1="inhibitor" variable_2="inhibitor"/>
</connection>
<connection>
<map_components component_1="EGFR_i" component_2="model_parameters"/>
<map_variables variable_1="EGF_binding_kf" variable_2="EGF_binding_kf"/>
<map_variables variable_1="EGF_binding_kb" variable_2="EGF_binding_kb"/>
<map_variables variable_1="inhibitor_binding_kf" variable_2="inhibitor_binding_kf"/>
<map_variables variable_1="inhibitor_binding_kb" variable_2="inhibitor_binding_kb"/>
<map_variables variable_1="EGFR_turnover" variable_2="EGFR_turnover"/>
</connection>
<connection>
<map_components component_1="EGF_EGFR_i" component_2="EGF"/>
<map_variables variable_1="EGF" variable_2="EGF"/>
</connection>
<connection>
<map_components component_1="EGF_EGFR_i" component_2="inhibitor"/>
<map_variables variable_1="inhibitor" variable_2="inhibitor"/>
</connection>
<connection>
<map_components component_1="EGF_EGFR_i" component_2="model_parameters"/>
<map_variables variable_1="EGF_binding_kf" variable_2="EGF_binding_kf"/>
<map_variables variable_1="EGF_binding_kb" variable_2="EGF_binding_kb"/>
<map_variables variable_1="inhibitor_binding_kf" variable_2="inhibitor_binding_kf"/>
<map_variables variable_1="inhibitor_binding_kb" variable_2="inhibitor_binding_kb"/>
</connection>
<connection>
<map_components component_1="pEGFR" component_2="EGF_EGFR"/>
<map_variables variable_1="EGF_EGFR" variable_2="EGF_EGFR"/>
</connection>
<connection>
<map_components component_1="pEGFR" component_2="pEGFR_Akt"/>
<map_variables variable_1="pEGFR" variable_2="pEGFR"/>
<map_variables variable_1="pEGFR_Akt" variable_2="pEGFR_Akt"/>
</connection>
<connection>
<map_components component_1="pEGFR" component_2="Akt"/>
<map_variables variable_1="pEGFR" variable_2="pEGFR"/>
<map_variables variable_1="Akt" variable_2="Akt"/>
</connection>
<connection>
<map_components component_1="pEGFR" component_2="model_parameters"/>
<map_variables variable_1="k1_pEGFR_degradation" variable_2="k1_pEGFR_degradation"/>
<map_variables variable_1="k1_Akt_phosphorylation" variable_2="k1_Akt_phosphorylation"/>
<map_variables variable_1="k1_EGFR_phosphorylation" variable_2="k1_EGFR_phosphorylation"/>
<map_variables variable_1="k1_pEGFR_Akt" variable_2="k1_pEGFR_Akt"/>
<map_variables variable_1="k2_pEGFR_Akt" variable_2="k2_pEGFR_Akt"/>
</connection>
<connection>
<map_components component_1="pEGFR_Akt" component_2="Akt"/>
<map_variables variable_1="pEGFR_Akt" variable_2="pEGFR_Akt"/>
<map_variables variable_1="Akt" variable_2="Akt"/>
</connection>
<connection>
<map_components component_1="pEGFR_Akt" component_2="model_parameters"/>
<map_variables variable_1="k1_Akt_phosphorylation" variable_2="k1_Akt_phosphorylation"/>
<map_variables variable_1="k1_pEGFR_Akt" variable_2="k1_pEGFR_Akt"/>
<map_variables variable_1="k2_pEGFR_Akt" variable_2="k2_pEGFR_Akt"/>
</connection>
<connection>
<map_components component_1="Akt" component_2="pAkt"/>
<map_variables variable_1="pAkt" variable_2="pAkt"/>
</connection>
<connection>
<map_components component_1="Akt" component_2="model_parameters"/>
<map_variables variable_1="k1_pAkt_dephosphorylation" variable_2="k1_pAkt_dephosphorylation"/>
<map_variables variable_1="k1_pEGFR_Akt" variable_2="k1_pEGFR_Akt"/>
<map_variables variable_1="k2_pEGFR_Akt" variable_2="k2_pEGFR_Akt"/>
</connection>
<connection>
<map_components component_1="pAkt" component_2="S6"/>
<map_variables variable_1="S6" variable_2="S6"/>
<map_variables variable_1="pAkt" variable_2="pAkt"/>
</connection>
<connection>
<map_components component_1="pAkt" component_2="pAkt_S6"/>
<map_variables variable_1="pAkt_S6" variable_2="pAkt_S6"/>
<map_variables variable_1="pAkt" variable_2="pAkt"/>
</connection>
<connection>
<map_components component_1="pAkt" component_2="pEGFR_Akt"/>
<map_variables variable_1="pEGFR_Akt" variable_2="pEGFR_Akt"/>
</connection>
<connection>
<map_components component_1="pAkt" component_2="model_parameters"/>
<map_variables variable_1="k1_Akt_phosphorylation" variable_2="k1_Akt_phosphorylation"/>
<map_variables variable_1="k1_pAkt_S6" variable_2="k1_pAkt_S6"/>
<map_variables variable_1="k2_pAkt_S6" variable_2="k2_pAkt_S6"/>
<map_variables variable_1="k1_S6_phosphorylation" variable_2="k1_S6_phosphorylation"/>
<map_variables variable_1="k1_pAkt_dephosphorylation" variable_2="k1_pAkt_dephosphorylation"/>
</connection>
<connection>
<map_components component_1="pAkt_S6" component_2="S6"/>
<map_variables variable_1="S6" variable_2="S6"/>
<map_variables variable_1="pAkt_S6" variable_2="pAkt_S6"/>
</connection>
<connection>
<map_components component_1="pAkt_S6" component_2="model_parameters"/>
<map_variables variable_1="k1_pAkt_S6" variable_2="k1_pAkt_S6"/>
<map_variables variable_1="k2_pAkt_S6" variable_2="k2_pAkt_S6"/>
<map_variables variable_1="k1_S6_phosphorylation" variable_2="k1_S6_phosphorylation"/>
</connection>
<connection>
<map_components component_1="S6" component_2="pS6"/>
<map_variables variable_1="pS6" variable_2="pS6"/>
</connection>
<connection>
<map_components component_1="S6" component_2="model_parameters"/>
<map_variables variable_1="k1_pAkt_S6" variable_2="k1_pAkt_S6"/>
<map_variables variable_1="k2_pAkt_S6" variable_2="k2_pAkt_S6"/>
<map_variables variable_1="k1_pS6_dephosphorylation" variable_2="k1_pS6_dephosphorylation"/>
</connection>
<connection>
<map_components component_1="pS6" component_2="pAkt_S6"/>
<map_variables variable_1="pAkt_S6" variable_2="pAkt_S6"/>
</connection>
<connection>
<map_components component_1="pS6" component_2="model_parameters"/>
<map_variables variable_1="k1_S6_phosphorylation" variable_2="k1_S6_phosphorylation"/>
<map_variables variable_1="k1_pS6_dephosphorylation" variable_2="k1_pS6_dephosphorylation"/>
</connection>
<connection>
<map_components component_1="pEGFR_total" component_2="pEGFR"/>
<map_variables variable_1="pEGFR" variable_2="pEGFR"/>
</connection>
<connection>
<map_components component_1="pEGFR_total" component_2="pEGFR_Akt"/>
<map_variables variable_1="pEGFR_Akt" variable_2="pEGFR_Akt"/>
</connection>
<connection>
<map_components component_1="pAkt_total" component_2="pAkt"/>
<map_variables variable_1="pAkt" variable_2="pAkt"/>
</connection>
<connection>
<map_components component_1="pAkt_total" component_2="pAkt_S6"/>
<map_variables variable_1="pAkt_S6" variable_2="pAkt_S6"/>
</connection>
<connection>
<map_components component_1="pS6_total" component_2="pS6"/>
<map_variables variable_1="pS6" variable_2="pS6"/>
</connection>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="">
<dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">
Decoupling of receptor and downstream signals in the Akt pathway by its low-pass filter characteristics: EGFR-inhibited Akt pathway model
</dc:title>
<dc:creator rdf:parseType="Resource">
<vCard:N rdf:parseType="Resource">
<vCard:Family>Lloyd</vCard:Family>
<vCard:Given>Catherine</vCard:Given>
<vCard:Other>May</vCard:Other>
</vCard:N>
<vCard:EMAIL rdf:parseType="Resource">
<rdf:value>c.lloyd@auckland.ac.nz</rdf:value>
<rdf:type rdf:resource="http://imc.org/vCard/3.0#internet"/>
</vCard:EMAIL>
<vCard:ORG rdf:parseType="Resource">
<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>Auckland Bioengineering Institute</vCard:Orgunit>
</vCard:ORG>
</dc:creator>
</rdf:Description>
<rdf:Description rdf:about="#fujita_2010">
<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>Akt</rdf:li>
</rdf:Bag>
</rdf:value>
</dc:subject>
</bqs:reference>
<bqs:reference rdf:parseType="Resource">
<bqs:Pubmed_id>20664065</bqs:Pubmed_id>
<bqs:JournalArticle rdf:parseType="Resource">
<dc:creator>
<rdf:Seq>
<rdf:li rdf:parseType="Resource">
<bqs:Person rdf:parseType="Resource">
<vCard:N rdf:parseType="Resource">
<vCard:Family>Fujita</vCard:Family>
<vCard:Given>K</vCard:Given>
<vCard:Other>A</vCard:Other>
</vCard:N>
</bqs:Person>
</rdf:li>
<rdf:li rdf:parseType="Resource">
<bqs:Person rdf:parseType="Resource">
<vCard:N rdf:parseType="Resource">
<vCard:Family>Toyoshima</vCard:Family>
<vCard:Given>Y</vCard:Given>
</vCard:N>
</bqs:Person>
</rdf:li>
<rdf:li rdf:parseType="Resource">
<bqs:Person rdf:parseType="Resource">
<vCard:N rdf:parseType="Resource">
<vCard:Family>Uda</vCard:Family>
<vCard:Given>S</vCard:Given>
</vCard:N>
</bqs:Person>
</rdf:li>
<rdf:li rdf:parseType="Resource">
<bqs:Person rdf:parseType="Resource">
<vCard:N rdf:parseType="Resource">
<vCard:Family>Ozaki</vCard:Family>
<vCard:Given>Y</vCard:Given>
</vCard:N>
</bqs:Person>
</rdf:li>
<rdf:li rdf:parseType="Resource">
<bqs:Person rdf:parseType="Resource">
<vCard:N rdf:parseType="Resource">
<vCard:Family>Kubota</vCard:Family>
<vCard:Given>H</vCard:Given>
</vCard:N>
</bqs:Person>
</rdf:li>
<rdf:li rdf:parseType="Resource">
<bqs:Person rdf:parseType="Resource">
<vCard:N rdf:parseType="Resource">
<vCard:Family>Kuroda</vCard:Family>
<vCard:Given>S</vCard:Given>
</vCard:N>
</bqs:Person>
</rdf:li>
</rdf:Seq>
</dc:creator>
<dc:title>
Decoupling of receptor and downstream signals in the Akt pathway by its low-pass filter characteristics
</dc:title>
<dcterms:issued rdf:parseType="Resource">
<dcterms:W3CDTF>2010-07-27</dcterms:W3CDTF>
</dcterms:issued>
<bqs:Journal rdf:parseType="Resource">
<dc:title>Science Signaling</dc:title>
</bqs:Journal>
<bqs:volume>3</bqs:volume>
<bqs:issue>132</bqs:issue>
</bqs:JournalArticle>
</bqs:reference>
</rdf:Description>
</rdf:RDF>
</model>
