Difference between revisions of "Extracellular signal-regulated kinase (ERK)"
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| + | {|align=right | ||
| + | |__TOC__ | ||
| + | |} | ||
| + | <h2> Description of the model </h2> | ||
| + | <!--[[File:L MAPK SignallingNetwork.png]]--> | ||
| + | <table width="100%"> | ||
| + | <tr> | ||
| + | <td style="vertical-align:top;"> | ||
| + | According to the topology which is found as most likely by Xu et al (2010)<ref name="Xu2010"> Tian-Rui Xu et al. (2010) "Inferring signaling pathway topologies from multiple perturbation measurements of specific biochemical species." ''Sci Signal.'' 3(134):ra20. ([http://www.ncbi.nlm.nih.gov/pubmed/20234003 pmid:20234003])</ref> a kinetic model is created. Literature data is used to estimate the parameter values and their uncertainty. <br> | ||
| + | This results in a probablitiy distribution for each parameter. According to these distributions samples were drawn and for each parameter composition a steady state analysis was performed. The result of this prcedure is that each output of the model is givn with a certain uncertainty. | ||
| − | [[ | + | For more information about previous applications for this kind of uncertainty modelling please refer to the publications listed [[#Previous Publications about uncertainty modelling|here]]. |
| − | + | ||
| − | + | ||
| − | + | Due to the literature data and the parameter measured, we changed the kinetics of some reactions and ended up in two different models: | |
| − | + | ||
| − | + | In one (non-modified model) only one reaction kinetic differs from Xu et al. (2010)<ref name="Xu2010"></ref>, the [[Sos-Binding|Sos-Activation]] (purple reaction) and is assumed be a binding process rather than enzyme catalysed. Furthermore we modelled the [[ERK-Activation]] as two step reaction, with the monophosphorylated ERK as intermediate. | |
| − | + | ||
| − | + | In the other one (modified model) further kinetics were changed in addition to these modifications (marked in red). So are the [[EPAC_and_PKA-Activation_(Agonist)|activation of EPAC and PKA by an agonist]] modelled as binding, [[C3G-Activation]] is modelled in two steps, first a binding to the receptor than a phosphorylation, and the [[Ras-Activation]] process is splitted in its elementary reactions, and their kinetics are therefore mass action. <br> | |
| − | + | The differentiation in two different models is made to gain one model which is as close as possible to Xu et al. (2010)<ref name="Xu2010"> Tian-Rui Xu et al. (2010) "Inferring signaling pathway topologies from multiple perturbation measurements of specific biochemical species." ''Sci Signal.'' 3(134):ra20. ([http://www.ncbi.nlm.nih.gov/pubmed/20234003 pmid:20234003])</ref> and another one, in which the reaction mechanism resemble the published one and therefore more measured parameter are available. | |
| − | + | ||
| − | + | ||
| − | + | The network topology is shown in the graph besides.<br> | |
| − | + | Click on a reaction to have more information about it. | |
| − | + | ||
| − | + | </td> | |
| − | + | <td> | |
| − | + | <div> | |
| − | + | ||
| − | + | <imagemap> | |
| − | + | File:L_MAPK_komplett.png|frameless|600px | |
| − | + | ||
| − | + | rect 130 435 179 467 [[C3G-Activation|C3G-Activation]] | |
| − | + | rect 80 352 112 384 [[EGF-Binding|EGF-Binding]] | |
| − | + | rect 138 246 184 290 [[Sos-Binding|Sos-Binding]] | |
| − | + | rect 88 181 114 208 [[Sos-Removal|Sos-Removal]] | |
| − | + | rect 144 189 168 209 [[Sos-Removal|Sos-Removal]] | |
| − | + | rect 189 186 230 209 [[Sos-Removal|Sos-Removal]] | |
| − | + | rect 300 185 339 216 [[Sos-Removal|Sos-Removal]] | |
| + | rect 362 71 390 102 [[ERK-Inactivation|ERK-Inactivation]] | ||
| + | rect 364 184 388 214 [[ERK-Inactivation|ERK-Inactivation]] | ||
| + | rect 418 186 445 208 [[ERK-Activation|ERK-Activation]] | ||
| + | rect 420 70 448 96 [[ERK-Activation|ERK-Activation]] | ||
| + | rect 527 133 601 151 [[Dephosphorylation|MEK-Inactivation]] | ||
| + | rect 646 306 665 458 [[Dephosphorylation|Raf1-Inactivation]] | ||
| + | rect 108 487 195 506 [[Dephosphorylation|C3G-Inactivation]] | ||
| + | rect 498 182 541 208 [[MEK-Activation(BRaf)|MEK-Activation(BRaf)]] | ||
| + | rect 638 185 671 209 [[MEK-Activation(Raf1)|MEK-Activation(Raf1)]] | ||
| + | rect 509 249 529 268 [[Dephosphorylation|BRaf-Inactivation]] | ||
| + | rect 499 290 526 311 [[BRaf_and_Raf1-Activation|BRaf-Activation(Ras)]] | ||
| + | rect 503 315 527 341 [[BRaf_and_Raf1-Activation|BRaf-Activation(Rap1)]] | ||
| + | rect 617 357 646 387 [[BRaf_and_Raf1-Activation|Raf1-Activation]] | ||
| + | rect 307 316 338 338 [[Ras-Activation|Ras-Activation]] | ||
| + | rect 309 402 341 424 [[RasRap1-Inactivation|Ras-Inactivation(GAP)]] | ||
| + | rect 360 503 388 528 [[RasRap1-Inactivation|Rap1-Inactivation]] | ||
| + | rect 302 486 334 515 [[Rap1-Activation|Rap1-Activation]] | ||
| + | rect 416 546 458 573 [[Rap1-Activation|Rap1-Activation]] | ||
| + | rect 425 666 454 694 [[EPAC_and_PKA-Activation_(Agonist)|EPAC-Activation(EPACA)]] | ||
| + | rect 665 665 691 698 [[EPAC_and_PKA-Activation_(Agonist)|PKA-Activation(PKA)]] | ||
| + | rect 498 667 528 698 [[EPAC_and_PKA-Activation_(Cilostamide)|EPAC-Activation(Cilostamide)]] | ||
| + | rect 621 669 646 694 [[EPAC_and_PKA-Activation_(Cilostamide)|PKA-Activation(Cilostamide)]] | ||
| + | rect 464 651 486 708 [[EPAC_and_PKA-Inactivation|EPAC-Inactivation]] | ||
| + | rect 647 652 658 706 [[EPAC_and_PKA-Inactivation|PKA-Inactivation]] | ||
| + | rect 637 541 677 573 [[Raf-1-Removal|Raf1-Removal]] | ||
| + | |||
| + | desc bottom-left | ||
| + | </imagemap> | ||
| + | </div> | ||
| + | |||
| + | </td> | ||
| + | </tr> | ||
| + | </table> | ||
| + | <h2>Reactions</h2> | ||
| + | |||
| + | <table width="50%"> | ||
| + | <tr> | ||
| + | <td> | ||
| + | * [[Dephosphorylation|BRaf-Inactivation]] | ||
| + | * [[BRaf and Raf1-Activation|BRaf-Activation(Rap1)]] | ||
| + | * [[BRaf and Raf1-Activation|BRaf-Activation(Ras)]] | ||
| + | * [[C3G-Activation]] | ||
| + | * [[Dephosphorylation|C3G-Inactivation]] | ||
| + | * [[EGF-Binding]] | ||
| + | * [[EPAC and PKA-Activation(Cilostamide)]] | ||
| + | * [[EPAC and PKA-Activation (Agonist)|EPAC-Activation(EPACA)]] | ||
| + | * [[EPAC and PKA-Inactivation|EPAC-Inactivation]] | ||
| + | * [[ERK-Activation]] | ||
| + | * [[ERK-Inactivation]] | ||
| + | * [[MEK-Activation(BRaf)|MEK-Activation(BRaf)]] | ||
| + | * [[MEK-Activation(Raf1)|MEK-Activation(Raf1)]] | ||
| + | * [[Dephosphorylation|MEK-Inactivation]] | ||
| + | </td> | ||
| + | <td> | ||
| + | * [[EPAC and PKA-Activation (Agonist)|PKA-Activation(PKAA)]] | ||
| + | * [[EPAC and PKA-Inactivation|PKA-Inactivation]] | ||
| + | * [[BRaf and Raf1-Activation|Raf-1-Activation]] | ||
| + | * [[Raf-1-Removal]] | ||
| + | * [[Dephosphorylation|Raf-1-Inactivation]] | ||
| + | * [[Rap1-Activation|Rap1-Activation(EPAC)]] | ||
| + | * [[Rap1-Activation|Rap1-Activation(C3G)]] | ||
| + | * [[RasRap1-Inactivation|Rap1-Inactivation(GAP)]] | ||
| + | * [[Ras-Activation]] | ||
| + | * [[RasRap1-Inactivation|Ras-Inactivation(GAP)]] | ||
| + | * [[Sos-Binding]] | ||
| + | * [[Sos-Removal|Sos-Removal (Sospp)]] | ||
| + | * [[Sos-Removal|Sos-Removal (Sosp)]] | ||
| + | </td> | ||
| + | </tr> | ||
| + | </table> | ||
| + | |||
| + | <h2>Model File </h2> | ||
| + | [[File:MAPK-PPA2.xml]] | ||
| + | |||
| + | <h2>Equilibrium constants</h2> | ||
| + | [[Equilibrium constants]] | ||
| + | |||
| + | <h2> Parameter Overview </h2> | ||
| + | [[Parameter Overview]] | ||
| + | |||
| + | <h2> Previous Publications about uncertainty modelling </h2> | ||
| + | *Achcar, F., Kerkhoven, E., Bakker, B., Barrett, M. & Breitling, R (2012). "Dynamic modelling under uncertainty: The case of Trypanosoma brucei energy metabolism." ''PLoS Computational Biology'', 8(1):e1002352 [http://www.ncbi.nlm.nih.gov/pubmed/22379410 pmid:22379410] | ||
| + | |||
| + | *Breitling R, Achcar F, Takano E. (2013) "Modeling challenges in the synthetic biology of secondary metabolism." ''ACS Synth Biol.'', 2(7):373-8. doi: 10.1021/sb4000228 [http://www.ncbi.nlm.nih.gov/pubmed/23659212 pmid:23659212] | ||
| + | |||
| + | *Achcar F, Barrett MP, Breitling R. (2013) "Explicit consideration of topological and parameter uncertainty gives new insights into a well-established model of glycolysis." ''FEBS J.'' 280(18):4640-51 [http://www.ncbi.nlm.nih.gov/pubmed/23865459 pmid:23865459] | ||
| + | |||
| + | *Kerkhoven EJ, Achcar F, Alibu VP, Burchmore RJ, Gilbert IH, Trybiło M, Driessen NN, Gilbert D, Breitling R, Bakker BM, Barrett MP. (2013) "Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei." ''PLoS Comput Biol.'' 9(12):e1003371. [http://www.ncbi.nlm.nih.gov/pubmed/24339766 pmid:24339766] | ||
| + | |||
| + | *[http://2013.igem.org/Team:Manchester/Enzyme Igem Team Manchester 2013] | ||
| + | |||
| + | <h2>References</h2> | ||
| + | <references/> | ||
Latest revision as of 09:15, 3 August 2014
Description of the model
|
According to the topology which is found as most likely by Xu et al (2010)[1] a kinetic model is created. Literature data is used to estimate the parameter values and their uncertainty. For more information about previous applications for this kind of uncertainty modelling please refer to the publications listed here.
Due to the literature data and the parameter measured, we changed the kinetics of some reactions and ended up in two different models: In one (non-modified model) only one reaction kinetic differs from Xu et al. (2010)[1], the Sos-Activation (purple reaction) and is assumed be a binding process rather than enzyme catalysed. Furthermore we modelled the ERK-Activation as two step reaction, with the monophosphorylated ERK as intermediate. In the other one (modified model) further kinetics were changed in addition to these modifications (marked in red). So are the activation of EPAC and PKA by an agonist modelled as binding, C3G-Activation is modelled in two steps, first a binding to the receptor than a phosphorylation, and the Ras-Activation process is splitted in its elementary reactions, and their kinetics are therefore mass action.
|
  |
Reactions
Model File
Equilibrium constants
Parameter Overview
Previous Publications about uncertainty modelling
- Achcar, F., Kerkhoven, E., Bakker, B., Barrett, M. & Breitling, R (2012). "Dynamic modelling under uncertainty: The case of Trypanosoma brucei energy metabolism." PLoS Computational Biology, 8(1):e1002352 pmid:22379410
- Breitling R, Achcar F, Takano E. (2013) "Modeling challenges in the synthetic biology of secondary metabolism." ACS Synth Biol., 2(7):373-8. doi: 10.1021/sb4000228 pmid:23659212
- Achcar F, Barrett MP, Breitling R. (2013) "Explicit consideration of topological and parameter uncertainty gives new insights into a well-established model of glycolysis." FEBS J. 280(18):4640-51 pmid:23865459
- Kerkhoven EJ, Achcar F, Alibu VP, Burchmore RJ, Gilbert IH, Trybiło M, Driessen NN, Gilbert D, Breitling R, Bakker BM, Barrett MP. (2013) "Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei." PLoS Comput Biol. 9(12):e1003371. pmid:24339766
References
- ↑ 1.0 1.1 1.2 Tian-Rui Xu et al. (2010) "Inferring signaling pathway topologies from multiple perturbation measurements of specific biochemical species." Sci Signal. 3(134):ra20. (pmid:20234003)
