- Author:
- Jeelean <jlim063@aucklanduni.ac.nz>
- Date:
- 2009-07-10 10:48:57+12:00
- Desc:
- Corrected citation details
- Permanent Source URI:
- https://staging.physiomeproject.org/workspace/brightman_fell_2000/rawfile/69e82cb0db0831779e8c75a67d3bea0d10ad53be/brightman_fell_2000.cellml
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<title>Differential feedback regulation of the MAPK cascade underlies the
quantitative differences in EGF and NGF signalling in PC12 cells</title>
<author>
<firstname>Jeelean</firstname>
<surname>Lim</surname>
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This is the initial translation of the model into CellML. Concentrations have been made dimensionless in order to balance units. The percentage activation variables used to produce the graphs in the paper have not yet been added to this model. The model can therefore run in Opencell and COR but does not reproduce the figures in the paper.
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ABSTRACT: Although epidermal growth factor (EGF) induces transient activation of Ras and the mitogen-activated protein kinase (MAPK) cascade in PC12 cells, whereas nerve growth factor (NGF) stimulates sustained activation, the basis for these contrasting responses is not known. We have developed a computer simulation of EGF-induced MAPK cascade activation, which provides quantitative evidence that feedback inhibition of the MAPK cascade is the most important factor in determining the duration of cascade activation. Hence, we propose that the observed quantitative differences in EGF and NGF signalling can be accounted for by differential feedback regulation of the MAPK cascade.
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The complete original paper reference is cited below:
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Differential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling in PC12 cells, Frances A. Brightman, David A. Fell, 2000,<emphasis>Federation of European Biochemical Societies Letters</emphasis>, 482(3), 169-174. <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/11024454">PubMed ID: 11024454</ulink>
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<minus/>
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<minus/>
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<ci>MEKP</ci>
<ci>MEKPP</ci>
</apply>
</apply>
<apply>
<plus/>
<ci>K_25</ci>
<ci>ERKP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v26">
<variable name="v26" units="first_order_rate_constant" public_interface="out"/>
<variable name="ERKPP" units="dimensionless" public_interface="in"/>
<variable name="V_26" units="first_order_rate_constant" initial_value="400000"/>
<variable name="K_26" units="dimensionless" initial_value="600000"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v26</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>V_26</ci>
<ci>ERKPP</ci>
</apply>
<apply>
<plus/>
<ci>K_26</ci>
<ci>ERKPP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v27">
<variable name="v27" units="first_order_rate_constant" public_interface="out"/>
<variable name="ERKPP" units="dimensionless" public_interface="in"/>
<variable name="ShcGS" units="dimensionless" public_interface="in"/>
<variable name="k27" units="first_order_rate_constant" initial_value="1.6"/>
<variable name="K_27" units="dimensionless" initial_value="600000"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v27</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>ERKPP</ci>
<ci>ShcGS</ci>
<ci>k27</ci>
</apply>
<apply>
<plus/>
<ci>K_27</ci>
<ci>ShcGS</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v28">
<variable name="v28" units="first_order_rate_constant" public_interface="out"/>
<variable name="GSP" units="dimensionless" public_interface="in"/>
<variable name="V_28" units="first_order_rate_constant" initial_value="75"/>
<variable name="K_28" units="dimensionless" initial_value="20000"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v28</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>V_28</ci>
<ci>GSP</ci>
</apply>
<apply>
<plus/>
<ci>K_28</ci>
<ci>GSP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v29">
<variable name="v29" units="first_order_rate_constant" public_interface="out"/>
<variable name="v_1" units="first_order_rate_constant" initial_value="1"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v29</ci>
<ci>v_1</ci>
</apply>
</math>
</component>
<component name="v30">
<variable name="v30" units="first_order_rate_constant" public_interface="out"/>
<variable name="t" units="dimensionless" public_interface="in"/>
<variable name="k_11" units="first_order_rate_constant" initial_value="0"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>v30</ci>
<apply>
<times/>
<ci>k_11</ci>
<ci>t</ci>
</apply>
</apply>
</math>
</component>
<connection>
<map_components component_1="Rs" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="RL" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Ri" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="L" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="R2L2" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="R2_CPP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Li" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="R2i" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Shc" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="ShcP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="ShcGS" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="GS" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="GSP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="RasGDP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Ras_ShcGS" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="RasGTP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="GAP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Ras_GAP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Raf" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Ras_Raf" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Rafa" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="MEK" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="MEKP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="MEKPP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="ERK" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="ERKP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="ERKPP" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="t" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="X" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Rs" component_2="v1"/>
<map_variables variable_1="Rs" variable_2="Rs"/>
<map_variables variable_1="v1" variable_2="v1"/>
</connection>
<connection>
<map_components component_1="Rs" component_2="v3"/>
<map_variables variable_1="Rs" variable_2="Rs"/>
<map_variables variable_1="v3" variable_2="v3"/>
</connection>
<connection>
<map_components component_1="RL" component_2="v1"/>
<map_variables variable_1="RL" variable_2="RL"/>
<map_variables variable_1="v1" variable_2="v1"/>
</connection>
<connection>
<map_components component_1="RL" component_2="v2"/>
<map_variables variable_1="RL" variable_2="RL"/>
<map_variables variable_1="v2" variable_2="v2"/>
</connection>
<connection>
<map_components component_1="RL" component_2="v4"/>
<map_variables variable_1="RL" variable_2="RL"/>
<map_variables variable_1="v4" variable_2="v4"/>
</connection>
<connection>
<map_components component_1="Ri" component_2="v2"/>
<map_variables variable_1="v2" variable_2="v2"/>
</connection>
<connection>
<map_components component_1="Ri" component_2="v3"/>
<map_variables variable_1="v3" variable_2="v3"/>
<map_variables variable_1="Ri" variable_2="Ri"/>
</connection>
<connection>
<map_components component_1="Ri" component_2="v6"/>
<map_variables variable_1="v6" variable_2="v6"/>
</connection>
<connection>
<map_components component_1="L" component_2="v1"/>
<map_variables variable_1="L" variable_2="L"/>
<map_variables variable_1="v1" variable_2="v1"/>
</connection>
<connection>
<map_components component_1="R2L2" component_2="v4"/>
<map_variables variable_1="R2L2" variable_2="R2L2"/>
<map_variables variable_1="v4" variable_2="v4"/>
</connection>
<connection>
<map_components component_1="R2L2" component_2="v5"/>
<map_variables variable_1="R2L2" variable_2="R2L2"/>
<map_variables variable_1="v5" variable_2="v5"/>
</connection>
<connection>
<map_components component_1="R2L2" component_2="v7"/>
<map_variables variable_1="R2L2" variable_2="R2L2"/>
<map_variables variable_1="v7" variable_2="v7"/>
</connection>
<connection>
<map_components component_1="R2L2" component_2="v9"/>
<map_variables variable_1="R2L2" variable_2="R2L2"/>
</connection>
<connection>
<map_components component_1="R2_CPP" component_2="v7"/>
<map_variables variable_1="R2_CPP" variable_2="R2_CPP"/>
<map_variables variable_1="v7" variable_2="v7"/>
</connection>
<connection>
<map_components component_1="R2_CPP" component_2="v8"/>
<map_variables variable_1="R2_CPP" variable_2="R2_CPP"/>
<map_variables variable_1="v8" variable_2="v8"/>
</connection>
<connection>
<map_components component_1="R2_CPP" component_2="v9"/>
<map_variables variable_1="R2_CPP" variable_2="R2_CPP"/>
</connection>
<connection>
<map_components component_1="Li" component_2="v2"/>
<map_variables variable_1="v2" variable_2="v2"/>
</connection>
<connection>
<map_components component_1="Li" component_2="v6"/>
<map_variables variable_1="v6" variable_2="v6"/>
</connection>
<connection>
<map_components component_1="R2i" component_2="v5"/>
<map_variables variable_1="v5" variable_2="v5"/>
</connection>
<connection>
<map_components component_1="R2i" component_2="v6"/>
<map_variables variable_1="R2i" variable_2="R2i"/>
<map_variables variable_1="v6" variable_2="v6"/>
</connection>
<connection>
<map_components component_1="R2i" component_2="v8"/>
<map_variables variable_1="v8" variable_2="v8"/>
</connection>
<connection>
<map_components component_1="R2i" component_2="v9"/>
<map_variables variable_1="R2i" variable_2="R2i"/>
</connection>
<connection>
<map_components component_1="Shc" component_2="v9"/>
<map_variables variable_1="Shc" variable_2="Shc"/>
<map_variables variable_1="v9" variable_2="v9"/>
</connection>
<connection>
<map_components component_1="Shc" component_2="v10"/>
<map_variables variable_1="v10" variable_2="v10"/>
</connection>
<connection>
<map_components component_1="ShcP" component_2="v10"/>
<map_variables variable_1="ShcP" variable_2="ShcP"/>
<map_variables variable_1="v10" variable_2="v10"/>
</connection>
<connection>
<map_components component_1="ShcP" component_2="v11"/>
<map_variables variable_1="ShcP" variable_2="ShcP"/>
<map_variables variable_1="v11" variable_2="v11"/>
</connection>
<connection>
<map_components component_1="ShcP" component_2="v27"/>
<map_variables variable_1="v27" variable_2="v27"/>
</connection>
<connection>
<map_components component_1="ShcGS" component_2="v11"/>
<map_variables variable_1="ShcGS" variable_2="ShcGS"/>
<map_variables variable_1="v11" variable_2="v11"/>
</connection>
<connection>
<map_components component_1="ShcGS" component_2="v13"/>
<map_variables variable_1="v13" variable_2="v13"/>
</connection>
<connection>
<map_components component_1="ShcGS" component_2="v27"/>
<map_variables variable_1="ShcGS" variable_2="ShcGS"/>
<map_variables variable_1="v27" variable_2="v27"/>
</connection>
<connection>
<map_components component_1="ShcGS" component_2="v12"/>
<map_variables variable_1="ShcGS" variable_2="ShcGS"/>
<map_variables variable_1="v12" variable_2="v12"/>
</connection>
<connection>
<map_components component_1="GS" component_2="v28"/>
<map_variables variable_1="v28" variable_2="v28"/>
</connection>
<connection>
<map_components component_1="GS" component_2="v11"/>
<map_variables variable_1="GS" variable_2="GS"/>
<map_variables variable_1="v11" variable_2="v11"/>
</connection>
<connection>
<map_components component_1="GSP" component_2="v27"/>
<map_variables variable_1="v27" variable_2="v27"/>
</connection>
<connection>
<map_components component_1="GSP" component_2="v28"/>
<map_variables variable_1="GSP" variable_2="GSP"/>
<map_variables variable_1="v28" variable_2="v28"/>
</connection>
<connection>
<map_components component_1="RasGDP" component_2="v15"/>
<map_variables variable_1="v15" variable_2="v15"/>
</connection>
<connection>
<map_components component_1="RasGDP" component_2="v12"/>
<map_variables variable_1="RasGDP" variable_2="RasGDP"/>
<map_variables variable_1="v12" variable_2="v12"/>
</connection>
<connection>
<map_components component_1="Ras_ShcGS" component_2="v12"/>
<map_variables variable_1="Ras_ShcGS" variable_2="Ras_ShcGS"/>
<map_variables variable_1="v12" variable_2="v12"/>
</connection>
<connection>
<map_components component_1="Ras_ShcGS" component_2="v13"/>
<map_variables variable_1="Ras_ShcGS" variable_2="Ras_ShcGS"/>
<map_variables variable_1="v13" variable_2="v13"/>
</connection>
<connection>
<map_components component_1="RasGTP" component_2="RasGDP"/>
<map_variables variable_1="RasGDP" variable_2="RasGDP"/>
</connection>
<connection>
<map_components component_1="RasGTP" component_2="v13"/>
<map_variables variable_1="v13" variable_2="v13"/>
</connection>
<connection>
<map_components component_1="RasGTP" component_2="v17"/>
<map_variables variable_1="v17" variable_2="v17"/>
</connection>
<connection>
<map_components component_1="RasGTP" component_2="v14"/>
<map_variables variable_1="RasGTP" variable_2="RasGTP"/>
<map_variables variable_1="v14" variable_2="v14"/>
</connection>
<connection>
<map_components component_1="RasGTP" component_2="v16"/>
<map_variables variable_1="RasGTP" variable_2="RasGTP"/>
<map_variables variable_1="v16" variable_2="v16"/>
</connection>
<connection>
<map_components component_1="GAP" component_2="v15"/>
<map_variables variable_1="v15" variable_2="v15"/>
</connection>
<connection>
<map_components component_1="GAP" component_2="v14"/>
<map_variables variable_1="GAP" variable_2="GAP"/>
<map_variables variable_1="v14" variable_2="v14"/>
</connection>
<connection>
<map_components component_1="Ras_GAP" component_2="v14"/>
<map_variables variable_1="Ras_GAP" variable_2="Ras_GAP"/>
<map_variables variable_1="v14" variable_2="v14"/>
</connection>
<connection>
<map_components component_1="Ras_GAP" component_2="v15"/>
<map_variables variable_1="Ras_GAP" variable_2="Ras_GAP"/>
<map_variables variable_1="v15" variable_2="v15"/>
</connection>
<connection>
<map_components component_1="Raf" component_2="v18"/>
<map_variables variable_1="v18" variable_2="v18"/>
</connection>
<connection>
<map_components component_1="Raf" component_2="v16"/>
<map_variables variable_1="Raf" variable_2="Raf"/>
<map_variables variable_1="v16" variable_2="v16"/>
</connection>
<connection>
<map_components component_1="Ras_Raf" component_2="v16"/>
<map_variables variable_1="Ras_Raf" variable_2="Ras_Raf"/>
<map_variables variable_1="v16" variable_2="v16"/>
</connection>
<connection>
<map_components component_1="Ras_Raf" component_2="v17"/>
<map_variables variable_1="Ras_Raf" variable_2="Ras_Raf"/>
<map_variables variable_1="v17" variable_2="v17"/>
</connection>
<connection>
<map_components component_1="Rafa" component_2="v18"/>
<map_variables variable_1="Rafa" variable_2="Rafa"/>
<map_variables variable_1="v18" variable_2="v18"/>
</connection>
<connection>
<map_components component_1="Rafa" component_2="v19"/>
<map_variables variable_1="Rafa" variable_2="Rafa"/>
<map_variables variable_1="v19" variable_2="v19"/>
</connection>
<connection>
<map_components component_1="Rafa" component_2="v21"/>
<map_variables variable_1="Rafa" variable_2="Rafa"/>
<map_variables variable_1="v21" variable_2="v21"/>
</connection>
<connection>
<map_components component_1="Rafa" component_2="v17"/>
<map_variables variable_1="v17" variable_2="v17"/>
</connection>
<connection>
<map_components component_1="MEK" component_2="v20"/>
<map_variables variable_1="v20" variable_2="v20"/>
</connection>
<connection>
<map_components component_1="MEK" component_2="v19"/>
<map_variables variable_1="v19" variable_2="v19"/>
<map_variables variable_1="MEK" variable_2="MEK"/>
</connection>
<connection>
<map_components component_1="MEKP" component_2="v19"/>
<map_variables variable_1="v19" variable_2="v19"/>
</connection>
<connection>
<map_components component_1="MEKP" component_2="v20"/>
<map_variables variable_1="v20" variable_2="v20"/>
<map_variables variable_1="MEKP" variable_2="MEKP"/>
</connection>
<connection>
<map_components component_1="MEKP" component_2="v21"/>
<map_variables variable_1="MEKP" variable_2="MEKP"/>
<map_variables variable_1="v21" variable_2="v21"/>
</connection>
<connection>
<map_components component_1="MEKP" component_2="v22"/>
<map_variables variable_1="v22" variable_2="v22"/>
</connection>
<connection>
<map_components component_1="MEKP" component_2="v23"/>
<map_variables variable_1="MEKP" variable_2="MEKP"/>
</connection>
<connection>
<map_components component_1="MEKP" component_2="v25"/>
<map_variables variable_1="MEKP" variable_2="MEKP"/>
</connection>
<connection>
<map_components component_1="MEKPP" component_2="v21"/>
<map_variables variable_1="v21" variable_2="v21"/>
</connection>
<connection>
<map_components component_1="MEKPP" component_2="v22"/>
<map_variables variable_1="MEKPP" variable_2="MEKPP"/>
<map_variables variable_1="v22" variable_2="v22"/>
</connection>
<connection>
<map_components component_1="MEKPP" component_2="v23"/>
<map_variables variable_1="MEKPP" variable_2="MEKPP"/>
</connection>
<connection>
<map_components component_1="MEKPP" component_2="v25"/>
<map_variables variable_1="MEKPP" variable_2="MEKPP"/>
</connection>
<connection>
<map_components component_1="ERK" component_2="v24"/>
<map_variables variable_1="v24" variable_2="v24"/>
</connection>
<connection>
<map_components component_1="ERK" component_2="v23"/>
<map_variables variable_1="ERK" variable_2="ERK"/>
<map_variables variable_1="v23" variable_2="v23"/>
</connection>
<connection>
<map_components component_1="ERKP" component_2="v23"/>
<map_variables variable_1="v23" variable_2="v23"/>
</connection>
<connection>
<map_components component_1="ERKP" component_2="v26"/>
<map_variables variable_1="v26" variable_2="v26"/>
</connection>
<connection>
<map_components component_1="ERKP" component_2="v24"/>
<map_variables variable_1="ERKP" variable_2="ERKP"/>
<map_variables variable_1="v24" variable_2="v24"/>
</connection>
<connection>
<map_components component_1="ERKP" component_2="v25"/>
<map_variables variable_1="ERKP" variable_2="ERKP"/>
<map_variables variable_1="v25" variable_2="v25"/>
</connection>
<connection>
<map_components component_1="ERKPP" component_2="v25"/>
<map_variables variable_1="v25" variable_2="v25"/>
</connection>
<connection>
<map_components component_1="ERKPP" component_2="v26"/>
<map_variables variable_1="ERKPP" variable_2="ERKPP"/>
<map_variables variable_1="v26" variable_2="v26"/>
</connection>
<connection>
<map_components component_1="ERKPP" component_2="v27"/>
<map_variables variable_1="ERKPP" variable_2="ERKPP"/>
</connection>
<connection>
<map_components component_1="t" component_2="v29"/>
<map_variables variable_1="v29" variable_2="v29"/>
</connection>
<connection>
<map_components component_1="t" component_2="v2"/>
<map_variables variable_1="t" variable_2="t"/>
</connection>
<connection>
<map_components component_1="t" component_2="v3"/>
<map_variables variable_1="t" variable_2="t"/>
</connection>
<connection>
<map_components component_1="t" component_2="v5"/>
<map_variables variable_1="t" variable_2="t"/>
</connection>
<connection>
<map_components component_1="t" component_2="v6"/>
<map_variables variable_1="t" variable_2="t"/>
</connection>
<connection>
<map_components component_1="t" component_2="v8"/>
<map_variables variable_1="t" variable_2="t"/>
</connection>
<connection>
<map_components component_1="t" component_2="v30"/>
<map_variables variable_1="t" variable_2="t"/>
</connection>
<connection>
<map_components component_1="X" component_2="v30"/>
<map_variables variable_1="v30" variable_2="v30"/>
</connection>
</model>
