{"database":"BioModels","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Pdf":["https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018.pdf"],"Svg":["https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018.svg"],"Owl":["https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018-biopax2.owl","https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018-biopax3.owl"],"Xml":["https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018_url.xml","https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018_urn.xml"],"Other":["https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018.sci","https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018.png","https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018.xpp","https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018.m","https://www.ebi.ac.uk/biomodels/model/download/MODEL1204280018?filename=MODEL1204280018.vcml"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"submitter":["Uddipan Sarma"],"curationStatus":["Non-curated"],"modellingApproach":["ordinary differential equation model"],"levelVersion":["L2V4"],"full_dataset_link":["https://www.ebi.ac.uk/biomodels/MODEL1204280018"],"publication_pubmed":["22748295"],"isPrivate":["false"],"repository":["BioModels"],"modelFormat":["SBML"],"omics_type":["Models"],"tokenised_name":["Sarma2012   Interaction topologies of MAPK cascade (M2 K2 USEQ)"],"publication_year":["2012"],"submissionId":["MODEL1204280018"],"publication_authors":["Uddipan Sarma, Indira Ghosh"],"first_author":["Uddipan Sarma"],"publication":["22748295,\n                            <h4>Background</h4>The three layer mitogen activated protein kinase (MAPK) signaling cascade exhibits different designs of interactions between its kinases and phosphatases. While the sequential interactions between the three kinases of the cascade are tightly preserved, the phosphatases of the cascade, such as MKP3 and PP2A, exhibit relatively diverse interactions with their substrate kinases. Additionally, the kinases of the MAPK cascade can also sequester their phosphatases. Thus, each topologically distinct interaction design of kinases and phosphatases could exhibit unique signal processing characteristics, and the presence of phosphatase sequestration may lead to further fine tuning of the propagated signal.<h4>Results</h4>We have built four architecturally distinct types of models of the MAPK cascade, each model with identical kinase-kinase interactions but unique kinases-phosphatases interactions. Our simulations unravelled that MAPK cascade's robustness to external perturbations is a function of nature of interaction between its kinases and phosphatases. The cascade's output robustness was enhanced when phosphatases were sequestrated by their target kinases. We uncovered a novel implicit/hidden negative feedback loop from the phosphatase MKP3 to its upstream kinase Raf-1, in a cascade resembling the B cell MAPK cascade. Notably, strength of the feedback loop was reciprocal to the strength of phosphatases' sequestration and stronger sequestration abolished the feedback loop completely. An experimental method to verify the presence of the feedback loop is also proposed. We further showed, when the models were activated by transient signal, memory (total time taken by the cascade output to reach its unstimulated level after removal of signal) of a cascade was determined by the specific designs of interaction among its kinases and phosphatases.<h4>Conclusions</h4>Differences in interaction designs among the kinases and phosphatases can differentially shape the robustness and signal response behaviour of the MAPK cascade and phosphatase sequestration dramatically enhances the robustness to perturbations in each of the cascade. An implicit negative feedback loop was uncovered from our analysis and we found that strength of the negative feedback loop is reciprocally related to the strength of phosphatase sequestration. Duration of output phosphorylation in response to a transient signal was also found to be determined by the individual cascade's kinase-phosphatase interaction design.. null, 6.\n                            National Centre for Cell Science, Ganeshkhind, Pune-7, India. uddipans@gmail.com"],"submitter_mail":["uddipans@gmail.com"],"submitter_affiliation":["National Centre for Cell Science"],"pubmed_abstract":["<h4>Background</h4>The three layer mitogen activated protein kinase (MAPK) signaling cascade exhibits different designs of interactions between its kinases and phosphatases. While the sequential interactions between the three kinases of the cascade are tightly preserved, the phosphatases of the cascade, such as MKP3 and PP2A, exhibit relatively diverse interactions with their substrate kinases. Additionally, the kinases of the MAPK cascade can also sequester their phosphatases. Thus, each topologically distinct interaction design of kinases and phosphatases could exhibit unique signal processing characteristics, and the presence of phosphatase sequestration may lead to further fine tuning of the propagated signal.<h4>Results</h4>We have built four architecturally distinct types of models of the MAPK cascade, each model with identical kinase-kinase interactions but unique kinases-phosphatases interactions. Our simulations unravelled that MAPK cascade's robustness to external perturbations is a function of nature of interaction between its kinases and phosphatases. The cascade's output robustness was enhanced when phosphatases were sequestrated by their target kinases. We uncovered a novel implicit/hidden negative feedback loop from the phosphatase MKP3 to its upstream kinase Raf-1, in a cascade resembling the B cell MAPK cascade. Notably, strength of the feedback loop was reciprocal to the strength of phosphatases' sequestration and stronger sequestration abolished the feedback loop completely. An experimental method to verify the presence of the feedback loop is also proposed. We further showed, when the models were activated by transient signal, memory (total time taken by the cascade output to reach its unstimulated level after removal of signal) of a cascade was determined by the specific designs of interaction among its kinases and phosphatases.<h4>Conclusions</h4>Differences in interaction designs among the kinases and phosphatases can differentially shape the robustness and signal response behaviour of the MAPK cascade and phosphatase sequestration dramatically enhances the robustness to perturbations in each of the cascade. An implicit negative feedback loop was uncovered from our analysis and we found that strength of the negative feedback loop is reciprocally related to the strength of phosphatase sequestration. Duration of output phosphorylation in response to a transient signal was also found to be determined by the individual cascade's kinase-phosphatase interaction design."],"pubmed_title":["Different designs of kinase-phosphatase interactions and phosphatase sequestration shapes the robustness and signal flow in the MAPK cascade."],"pubmed_authors":["Sarma Uddipan U, Ghosh Indira I"],"name_synonyms":["MAPK signaling., MAPKKK cascade during sporulation, ERK/MAPK cascade, MAPK signalling"],"pubmed_abstract_synonyms":["Identical, ERBB2 Gene Amplification Negative, DmErk, PR53, B Cells, pp44mapk, PR55, Phosphatase, CDH1 Wild-Type, Cytogenetically Normal, CEK Gene Mutation Negative, BCC7 Gene Mutation Negative, B cell, ESTRB Negative, REMOVAL, Sequential, ECT1 Gene Rearrangement Negative, raf, phosphorylation, TRT Promoter Mutation Negative, DmelCG7109, B', GNA11 Gene Mutation Negative, Normal Tissue, l(3)S031807, ATP-protein transphosphorylase activity, PP2A 28D, Met Proto-Oncogene (Hepatocyte Growth Factor Receptor) Gene Amplification Negative, responsivity, node-negative, Related, Activate, Kinase, BRAF Wildtype, H. pylori Negative, SEM, Hepatitis B Virus Core Antibody Negative, No rearrangement detected, HER2/neu Gene Mutation Negative, Pp2A, PP2a, l(3)S026226, ESR Negative, FGFBR Gene Mutation Negative, l(3)S027313, KGFR Gene Mutation Negative, PDCD1L1 Negative, N, Tissue, aar, Dsor2, cell sheath, Complete Agreement, Output, MET Amplification Negative, Phosphomonoesterases, HER2 Non-Amplified, D-raf1, PGR Negative, l(3)02414, DmelCG6235, ATRX Mutation Negative, XNP Gene Mutation Negative, PR65, PP2A, Taken, FMS-Like Tyrosine Kinase 2 Gene Rearrangement Negative, PAX8 Gene Rearrangement Negative, l(3)S048006, l(3)S048013, CG14080, CG14081, FGFR1 Rearrangement Negative, Relationship, ERK-A, dpERK, TP53 Gene Mutation Negative, Anti-HBc Negative, Serum CA 19-9 Normal, betaIIPKC, TP53 Mutation Negative, Longterm Effect, BRAF wt, DmMAPK, Normal skin, l(3)S091905, Normalcy, dp-ERK, cRaf, CDISC SEND Study Design Terminology., 1p/19q Co-deletion Negative, PP2-AB, Wee-kinase activity, Human Immunodeficiency Virus Negative, TMEM16A Negative, CTNNB1 Wildtype, pMAPK, DmPp2A-28D, Diverse, SEND-DESIGN, LCAM Gene Mutation Negative, Flavoprotein Subunit of Complex II Negative, Ret Proto-Oncogene Rearrangement Negative, FGFR3 Wild-Type, Migrants and Transients, l(1)pole hole, Model System, CRAF, Definite Attribution, pp2A-B', l(2)41Ac, Androgen Receptor Negative, B7-H Negative, D-raf, Present, c-KIT Negative, CT34260, l(3)S075902b, Phosphohydrolase, p16INK4a Negative, v-Ets Erythroblastosis Virus E26 Oncogene Like Gene Rearrangement Negative, CMD1NN, dpERk, signaling pathway, A/PR65, ATRX Gene Mutation Negative, B-Lymphocyte, l(3)S027127, Phosphoric, Unmethylated O-6-Methylguanine-DNA Methyltransferase Gene Promoter, EBV Negative, SAPK, TRP53 Gene Mutation Negative, Migrants, B7H1 Negative, Feedbacks, Wee 1-like kinase activity, Hepatitis B Core Antibody Negative, dPP2A-B56-1, dPP2A-B56-2, glycogen synthase kinase 3 activity, HER-2 Gene Mutation Negative, B-RAF1 Gene Rearrangement Negative, number, Alpha Thalassemia/Mental Retardation Syndrome X-Linked Gene Mutation Negative, CG5643, DRaf, Anti-HBc Antibody Negative, Succinate Dehydrogenase [Ubiquinone] Iron-Sulfur Subunit, Hidden, l(3)S132907, pyst1, SDHF Negative, l(3)S069206a, relational shape quality, BRCA1 Associated Protein 1 Gene Mutation Negative, K-SAM Gene Mutation Negative, Nuclear Receptor Subfamily 3 Group A Member 2 Negative, N-SAM Gene Rearrangement Negative, NRAS Wildtype, ribosomal protein S6 kinase II activity, CD333 Gene Mutation Negative, Expression Negative, KRAS Wildtype, GNA11 Wild-Type, ETV Rearrangement Negative, D-Raf, l(3)S119908, Erk, ESR1 Negative, c-MET Gene Amplification Negative, protein-serine kinase activity, l(3)S046918, Cadherin-Associated Protein, In, B-RAF1 Gene Mutation Negative, PP2A[B'-1], Longterm, l(3)S088513, Tissues, dPP2A-Balpha, FGFR1 Gene Mutation Negative, FGFR-2 Gene Mutation Negative, CDH1 Mutation Negative, STK32, PCBC, Target, Phl, FGFR-2 Gene Rearrangement Negative, SDHA Negative, BEST:LD02456, KRAS2 Gene Mutation Negative, erk, PP2A[B'-2], Alpha 11 Gene Mutation Negative, RAD54 Homolog Gene Mutation, l(3)S029110, Estrogen Receptor Alpha Negative, ETV Family Rearrangement Negative, FLT2 Gene Mutation Negative, Keratinocyte Growth Factor Receptor Gene Rearrangement Negative, ERBB2 wt, rll, p53 Gene Mutation Negative, Draf, Completion, HBsAg Negative, STK26, p38-2, myelin basic protein kinase activity, NORMAL, New, Hepatitis B Virus Surface Antibody Negative, CG 7913, Q Polypeptide Gene Mutation Negative, DRT, mkp-3, Fibroblast Growth Factor Receptor 1 Gene Rearrangement Negative, ETS Transcription Factor ERG Gene Rearrangement Negative, Harvey Rat Sarcoma Viral Oncogene Homolog Gene Mutation Negative, stress-activated kinase activity, SDHIP Negative, MAP-2 kinase activity, function, FGFR2 Wild-Type, Negative Number, verification, protein phosphokinase activity, Beta Catenin Gene Mutation Negative, del(10q23)/PTEN Gene Locus Deletion Negative, SRK2D, CTNNB1 Gene Mutation Negative, ATRX, experimental_method, stress-activated protein kinase activity, Long Term Effects, chemical analysis, PP2A C, Reaching, PP2A A, TP53 wt, Alpha-11 Gene Mutation Negative, activate, Hepatitis B Surface Protein Antigen Negative, NEGATIVE, protein kinase p58 activity, Fully Agree, serine/threonine protein kinase activity, Paired Domain Gene 8 Gene Rearrangement Negative, Definitely Related to Intervention, BEK Gene Mutation Negative, CG12559, Unmethylated MGMT Promoter, DmelCG17291, dpERK1, l(3)S032303, Dmkp3, Bursa-Equivalent Lymphocyte, dsk1, atypical PKC activity, tws/aar, Phytomitogens, ERBB2 Wildtype, No, l(1)polehole/draf, Differential, Lack of Expression of PD-L1, Catenin Beta 1 Gene Mutation Negative, Specific, target lesion, Succinate Dehydrogenase [Ubiquinone] Flavoprotein Subunit, PROTEIN KINASE, protein serine-threonine kinase activity, Fine, SAP kinase activity, Pp2A29B, Anti-Hepatitis B Core Antibody Negative, glycogen synthase kinase activity, LFS1 Gene Mutation Negative, protein kinase A activity, Normal Male External Genitalia, BAP1 Wildtype, Telomerase Reverse Transcriptase Gene Promoter Mutation Negative, DmelCG7913, Bursa-Dependent Lymphocytes, Feature, Mpk2, Activated, p42mapk, l(3)S060804, Human Herpesvirus-4 Negative, SR2-1, l(3)S025806, Hydrolase, kinase-related transforming protein, Tws, 0318/07, l(3)S031006, l(3)S053011, ESR2 Negative, l(3)S080409, ORAOV2 Negative, Definite, ATRX Wildtype, BRAF Mutation Negative, DESIGN, ESR-Beta Negative, l(3)s1801, CD274 Negative, DERK-A, Keratinocyte Growth Factor Receptor Gene Mutation Negative, Association, E(sina)7, Craf1, BAP1 wt, Rl, Raf kinase activity, PAX8 Rearrangement Negative, Novel, How Often Felt Normal, MP kinase activity, serine kinase activity, Chromatin Remodeler Gene Mutation Negative, FGFR-1 Gene Rearrangement Negative, v158, B lymphocyte, atypical protein kinase C activity, Had, Erb-B2 Receptor Tyrosine Kinase Gene Mutation Negative, MAPKKK cascade during sporulation, R75353, Normal, F20P5.30, None detected, Squatters, mitogen-activated S6 kinase activity, protein-aspartyl kinase activity, BAP1 Wild-Type, dERK, EXTRACTING, Analytical Procedure Robustness, ER-Alpha Negative, Has, Long-Term Effects, None Detected, SDHB Loss, l(3)S043029, F20P5_30, Ha-ras Gene Mutation Negative, GNA-11 Gene Mutation Negative, GNAQ Wildtype, HBsAb Negative, Mapk, l(3)S025832, FGFR-1 Gene Mutation Negative, lamina, CG7109, ERK1, ERK2, mapk1a, B/PR55, Negative, l(3)S101413b, Pp2A-85F, results, FLT-2 Gene Mutation Negative, BRAF Wild Type, M phase-specific cdc2 kinase activity, signaling cascade, Ets Variant Gene Family Rearrangement Negative, ESRA Negative, l(3)S110008a, FGFR3 Rearrangement Negative, KAL2 Gene Mutation Negative, mapk1b, MapK, ESTRR Negative, Workers, Adverse Event Related to Intervention, Fibroblast Growth Factor Receptor 2 Gene Mutation Negative, erk2, BcDNA:LD34343, FGFR2 Mutation Negative, l(1)G0475, ptpa, PP2A B', p16INK4 Negative, ERKa, phosphorylase B kinase kinase activity, Guanine Nucleotide Binding Protein (G Protein), BcDNA:RE08694, l(2R)EMS45-39, HHV-4 Negative, Draf1, HRAS Gene Mutation Negative, raf1, CAPB, PTPA, E-Cadherin Gene Mutation Negative, DmelCG12559, p38, CG6235, l(3)S061915, estrogen receptor negative, Features, Robustness, CG33297, 1p/19q Intact, HER2 Wildtype, Cascade, DpErk, l(3)S032708c, ERKA, SNF1-RELATED PROTEIN KINASE 2-2, hydroxyalkyl-protein kinase activity, FLT-2 Gene Rearrangement Negative, WEE1Hu, l(3)S023206, experimental strategy, MAPK signalling, l(3)S022361, C110, Tumor Protein p53 Gene Mutation Negative, Unmethylated MGMT Gene Promoter, Hydrolases, experimental_strategy, PR Negative, rafl, Normal Chest Appearance, Full Agreement, calcium/phospholipid-dependent protein kinase activity, KAL2 Gene Rearrangement Negative, tissue, GAQ Gene Mutation Negative, Negative Finding, v-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog Negative, Wdb, dPP2A, dPR55, JKT4 Gene Mutation Negative, Preservation, FGFR1 Wildtype, l(3)S048507, Hek5, Degree, Neuroblastoma RAS Viral Oncogene Homolog Gene Mutation Negative, OGD Gene Mutation Negative, Relations, SDHB Deficient, Anti-Hepatitis B Virus Surface Antibody Negative, dB56-2, c-K-ras Gene Mutation Negative, dB56-1, BcDNA:GM05554, T-antigen kinase activity, MET Proto-Oncogene, Mitochondrial Negative, galactosyltransferase-associated kinase activity, PP2A-A, reactivity, PP2A-B, l(3)S022205b, PP2A-C, Diversity, NR3A1 Negative, PRESENT, HHV4 Negative, DmelCG2845, NRAS Wild-Type, layer, GNA11 Wildtype, Transients, Normal Gait, Nonmigrants, G-ALPHA-q Gene Mutation Negative, Transphosphorylase, PDL1 Negative, CG18732, FGFR1 Gene Rearrangement Negative, CD331 Gene Mutation Negative, p16(INK4a) Negative, Squatter, protein kinase (phosphorylating) activity, signalling pathway, Erg-3 Gene Rearrangement Negative, l(1)raf, Verification, Found, Normal Abdomen on Visual Inspection, N-RAS Gene Mutation Negative, Long-Term Effect, Characteristics, casein kinase (phosphorylating) activity, Possess, KGFR Gene Rearrangement Negative, Removal, CD332 Gene Rearrangement Negative, ert1, Succinate Dehydrogenase Complex Flavoprotein Subunit A Negative, target_lesion, l(3)S060203, FLG Gene Rearrangement Negative, Beta Gene Mutation Negative, FGFR3 Gene Mutation Negative, l(3)S023013, Targeted, FGFR1 Mutation Negative, Normal Precordial Palpation Finding, l(3)S028707, Reciprocal, Related Attribution, l(3)S052810, Anti-HBs Antibody Negative, count in organism, 2.7.11.1, AP50 kinase activity, GNA11 wt, MBP kinase I activity, Xp42, Phosphoric Monoester, Anoctamin-1 Negative, ER Beta Negative, SPK-2-2, Exhibit, UVO Gene Mutation Negative, ERBB2 Mutation Negative, Normality, Kinases, mitogen activated kinase activity, FGFR3 wt, Su(Raf)2B, Succinate Dehydrogenase Complex Iron Sulfur Subunit B Negative, mkp3, COMPLETE, phosphoric monoester hydrolase activity, KIT Negative, PYST1, ERA Negative, OGD Gene Rearrangement Negative, B-RAF Gene Mutation Negative, CTNNB1 wt, Calcium-Dependent Adhesion Protein, Absent, introduction, SDH1 Negative, NEU Gene Amplification Negative, D-ERK, GTPase Gene Mutation Negative, CD324 Gene Mutation Negative, B7 Homolog 1 Negative, D830050J10Rik, Processing Technique, layer of cells, IDH wt Allele, 2414, BAP1 Gene Mutation Negative, RAF, Preserved, MAP kinase 1 activity, A-kinase activity, PP2A[[C]], extracellular signal-regulated kinase activity, l(3)S026326, Tyro5, CDKN2A-p16(INK4a) Negative, Cyclin-Dependent Kinase 4 Inhibitor A Negative, Design, Hepatitis B Surface Antigen Negative, PP2A[B], pr53, anon-WO0118547.420, group sequential design, GNAQ Gene Mutation Negative, CDH1 Wildtype, Verify, Story, UCHL2 Gene Mutation Negative, Long Term, Prp4 protein kinase activity, MKP3, LeMPK3, Nuclear Receptor Subfamily 3 Group A Member 1 Negative, GNAQ Mutation Negative, Progesterone Receptor Negative, p44mpk, FGFR-3 Gene Mutation Negative, H-ras Gene Mutation Negative, Normal Appearance of the Extremities, ATP:protein phosphotransferase (non-specific) activity, C-HA-RAS1 Gene Mutation Negative, Dp38, PP2A[C], CDKN2A-p16 Negative, SAPK2, l(3)01436, Sem, v-raf Murine Sarcoma Viral Oncogene Homolog B1 Gene Rearrangement Negative, l(3)S110815, MAP-k, average, HRas Proto-Oncogene, Loss of Expression, BFGFR Gene Rearrangement Negative, pp42, Draf-1, EK5, Completely Able, Nonmigrant, l(3)S141309, HBcAb Negative, COMPLETED, Isocitrate Dehydrogenase (NADP+) Gene Family Wildtype, Cytogenetic Abnormalities Absent, IP Negative, Normality-Based Dosing Unit, sem, pp2a, Transient, Normal Capillary Refill Time, l(3)S035505b, Anti-HBsAb Negative, Receptor Tyrosine Kinase Gene Amplification Negative, Catenin Beta-1 Gene Mutation Negative, Pp2A-28D, ATP Phosphotransferases, Negative Charge, phosphatase, HBs Antigen Negative, PP2A[A], p82 kinase activity, FGFR-3 Gene Rearrangement Negative, ER Alpha Negative, ERB Negative, ERBB2 Wild-Type, FGFR1 wt, l(3)S067915, dpErk, CDH1 Gene Mutation Negative, l(1)phl, Index, Difference, B Lymphocytes, CG7901, PMK-2, PMK-1, PMK-3, Extracted, GNA11 Mutation Negative, serine/threonine protein phosphatase 2A, CD117 Negative, Cadherin, 1466/06, pMapK, l(3)S029403, Helicobacter pylori Negative, v-Raf, l(3)S033903, Arc-1 Gene Mutation Negative, CG7913, DmERKA, rl/MAPK, Wrd, Epstein Barr Virus Negative, EST2 Promoter Mutation Negative, HGFR Gene Amplification Negative, Guanine Nucleotide-Binding Protein, l(3)S042630, Processing, HRAS Mutation Negative, v-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 Gene Amplification Negative, non-specific serine/threonine protein kinase activity, l(1)polehole, Beta-Catenin Gene Mutation Negative, ATRX wt, Anti-Hepatitis B Virus Core Antibody Negative, dPP2A A, HBs Negative, TERT Promoter Mutation Negative, ERG Gene Rearrangement Negative, wrd, SNF1-related protein kinase 2.2, serine-specific protein kinase activity, GNAQ wt, l(3)S066813, CDHE Gene Mutation Negative, HIPK2, cytidine 3', CTNNB Gene Mutation Negative, B56-2, MET Gene Amplification Negative, KRAS Gene Mutation Negative, EG:BACH48C10.3, BB129353, l(3)S042629, BRAF Gene Mutation Negative, B56-1, Epstein-Barr Virus Negative, c-Met Amplification Negative, l(3)S063110, LD02456, DmelCG14080, HER2 Gene Mutation Negative, G Protein Subunit Alpha q Gene Mutation Negative, glycogen synthase A kinase activity, Not Expressed, Effects, Remove, Different, 12559, Negative Estrogen Receptor, HER2 wt, Determine, model, draf, phosphorylase b kinase kinase activity, EK2-1, ER-, Completely Agree, l(3)S023141a, CMC1 Gene Mutation Negative, FGFBR Gene Rearrangement Negative, Li-Fraumeni Syndrome Gene Mutation Negative, CG17291, i234, IDH Family Gene Mutation Negative, NRAS Gene Mutation Negative, D-RAF, ERK, Negative Lymph Node, PRKM1, Normalities, l(3)j11C8, PRKM2, Normal Skin, Complete, Activation, FGFR3 Mutation Negative, MAPK signaling, JKT4 Gene Rearrangement Negative, ZNF-HX Gene Mutation Negative, GA11 Gene Mutation Negative, Ets Variant Family Rearrangement Negative, Paired Box Gene 8 Gene Rearrangement Negative, dPP2A-C, Long-Term, Worker, 5559, PDCD1LG1 Negative, NEU Gene Mutation Negative, Phosphoric Monoester Hydrolase, DPR65, protein-cysteine kinase activity, del10q23/Phosphatase and Tensin Homolog Gene Locus Negative, CTNNB1 Wild-Type, Hpr kinase activity, NEG, ER-Beta Negative, BRCA1-Associated Protein 1 Gene Mutation Negative, Programmed Cell Death 1 Ligand 1 Negative, BFGFR Gene Mutation Negative, PP2Ac, ppp2r2c, l(3)S076415, TCS1 Promoter Mutation Negative, HER2/neu Gene Amplification Negative, l(3)S023938, DPR55, Epithelial Gene Mutation Negative, FGFR3 Wildtype, EP3559, raf-1, Phosphorylations, protein serine kinase activity, CTNNB1 Mutation Negative, Hepatocyte Growth Factor Receptor Gene Amplification Negative, TERT Gene Promoter Mutation Negative, PKA, DmelCG5643, PKC, Have, mapk2, mapk1, KRAS Wild-Type, ATRX Wild-Type, CD333 Gene Rearrangement Negative, background, KIT Proto-Oncogene Tyrosine Protein Kinase Negative, signalling cascade, AA990557, Mitogen, DMKP-3, ESRB Negative, B-RAF Gene Rearrangement Negative, 1300019I03Rik, Destination, RET Rearrangement Negative, BRAF Rearrangement Negative, l(2)02496, IDH Mutation Negative, Erb-B2 Receptor Tyrosine Kinase Gene Amplification Negative, p16 Negative, PD-L1 Negative, HER2 Gene Amplification Negative, l(2)s5286, Fibroblast Growth Factor Receptor 1 Gene Mutation Negative, l(3)S075110, Normal Appearance of Extremities, Normal Capillary Refill, RAD54L Gene Mutation Negative, 5'-cyclic monophosphate-responsive protein kinase activity, Longterm Effects, l(3)S105605, Reach, Fibroblast Growth Factor Receptor 3 Gene Rearrangement Negative, dpMAPK, IDP Gene Mutation Negative, ppp2r2b-a, NRAS Mutation Negative, CDH1 wt, ETV Family Gene Rearrangement Negative, Nomads, sheath of cells, ANO1 Negative, FGFR1 Wild-Type, p16-INK4 Negative, ph, Completed, CEK Gene Rearrangement Negative, Group Sequential Design, c-Raf, l(3)S025913, determination, ERK/MAPK cascade, SWS Gene Mutation Negative, G Protein Subunit Alpha 11 Gene Mutation Negative, ER Negative, Usually Need Help from Another Person for Reach, experimental method, Verified, BRAF Gene Rearrangement Negative, l(3)S024838, Phosphatases, l(3)S045519, Completely, l(3)S043008b, FLG Gene Mutation Negative, PP2, mitogen-activated protein kinase activity, HRAS Wild-Type, Human Herpesvirus 4 Negative, mpk1, Effect, BAP1 Mutation Negative, Experimental Method, CD332 Gene Mutation Negative, Targeting, Erk/Map kinase, No mutation detected, Migrant Worker, l(3)S049902, p55 Gene Rearrangement Negative, Determination, Cyclin-Dependent Kinase Inhibitor 2A Negative, l(3)S067109b, TYPE 2A SERINE/THREONINE PROTEIN PHOSPHATASE, CD331 Gene Rearrangement Negative, MTS/PP2A, DERK, PR-, TP53 Wildtype, FGFR2 Gene Rearrangement Negative, Estrogen Receptor 2 Negative, FGFR2 Gene Mutation Negative, MBP kinase II activity, CD274 Molecule Negative, ER2-6, ATP, SDH2 Negative, v-Ha-ras Harvey Rat Sarcoma Viral Oncogene Homolog Gene Mutation Negative, Normal Thoracic Appearance, single-organism behavior, TARGET, negative test result, l(3)S024834a, tw, PP2a 28D, 6430402F14Rik, MAP kinase 2 activity, FMS-Like Tyrosine Kinase 2 Gene Mutation Negative, Estrogen Receptor 1 Negative, Determined, XH2 Gene Mutation Negative, l(3)S022440, Paired Box 8 Gene Rearrangement Negative, Hepatitis B Surface Antibody Negative, Erk1, Normal Reference Range, NR3A2 Negative, l(3)S023309, HRAS wt, MAPK, Migrant, NOS, Estrogen Receptor Negative, Conflict, Adverse Event Definitely Related to Intervention, Agree Completely, serine protein kinase activity, DRaf1, mapk, Study Design, Normal Immune Presence, ETV Gene Rearrangement Negative, l(3)S029701a, IDH Gene Family Wildtype, Transphosphorylases, HER-2 Gene Amplification Negative, ERBB2 Gene Mutation Negative, protein glutamyl kinase activity, RASH1 Gene Mutation Negative, IDH Gene Mutation Negative, Isocitrate Dehydrogenase Gene Family Wild Type, GNAQ Wild-Type, 10q23/PTEN Locus Deletion Negative, BEK Gene Rearrangement Negative, Presence, DpERK, l(3)S066017, ErkA, ECAD Gene Mutation Negative, Health, DOG1 Negative, epsilon PKC, l(3)S134601a, v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog Gene Mutation Negative, FGFR2 Wildtype, Hepatitis B Virus Surface Antigen Negative, l(3)S061805, Protein Kinase, pERK, CDISC SEND Study Design Terminology, ribosomal S6 protein kinase activity, LOST, v-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 Gene Mutation Negative, HH19, GroupII, PP2A-29B, NS5, IDH Family Wildtype, l(3)S075515b, Monoester Hydrolase, l(3)S111515, ECT1 Gene Mutation Negative, CG13383, presence, Migrant Workers, Anti-HBcAb Negative, FGFR2 wt, Proto-oncogene c-RAF, FLT2 Gene Rearrangement Negative, CD274 Antigen Negative, Phytomitogen, HRAS Wildtype, serine(threonine) protein kinase activity, Fp Negative, Negative Test Result, Anti-HBs Negative, Models, Level, Phosphotransferase, Raf1, FGFR3 Gene Rearrangement Negative, N-SAM Gene Mutation Negative, B'/PR61, Modeling System, B-cell, SDHB Deficiency, 1p/19q Codeletion Negative, l(3)S146606, xp42, Mast/Stem Cell Growth Factor Receptor Kit Negative, p42 mitogen-activated protein kinase activity, ATP-protein phosphotransferase, RAD54 Gene Mutation Negative, ATP:protein phosphotransferase (MAPKK-activated) activity, SNRK2-2, TISSUE, Raf-1, l(3)S024455, Cascade Device, DmERK-A, Model, Cadherin 1 Gene Mutation Negative, v-raf Murine Sarcoma Viral Oncogene Homolog B1 Gene Mutation Negative, AR Negative, Target Lesion Identification, RET Gene Rearrangement Negative, HIV Negative, NRAS wt, KRAS-2 Gene Mutation Negative, Mts, del(1p/19q) Negative, prkm2, prkm1, CT39192, l(1)2Fe, Certain, FGFR2 Rearrangement Negative, ERBB2 Non-Amplified, Fibroblast Growth Factor Receptor 3 Gene Mutation Negative, Extraction, Phosphotransferases, KRAS wt, TP2 Promoter Mutation Negative, p38delta, Phosphomonoesterase, twitchin kinase activity, Raf/phl, Characteristic, IDH Wild Type, Normal Point of Maximum Impulse, HER2 Wild-Type, Protein, Nomad, Fibroblast Growth Factor Receptor 2 Gene Rearrangement Negative, ERG Rearrangement Negative, K-SAM Gene Rearrangement Negative, threonine-specific protein kinase activity, progesterone receptor negative, distinct, MGMT Gene Promoter Methylation Negative, EY2-2, Unit of Concentration, RET/PTC Rearrangement Negative, l(1)ph, Unmethylated Methylguanine-DNA Methyltransferase Gene Promoter, SEQUENTIAL, No abnormality detected, 11-29, Phosphohydrolases, Specified, Floor, Estrogen Receptor Beta Negative, EPHT3, SDHB Negative, 6330556D22Rik, assay, Raf, response, Total, MKP-3, B-lymphocyte, TAOS2 Negative, CG2845"],"description_synonyms":["extent, PP2A[[C]], DmErk, extracellular 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completeness, CG7901, betaIIPKC, Longterm Effect, DmMAPK, dephosphorylation, PMK-2, l(3)S091905, dp-ERK, PMK-1, Procedure, cRaf, PP2-AB, PMK-3, ACMICD, Wee-kinase activity, serine/threonine protein phosphatase 2A, Public Domain, 1466/06, Domains, pMAPK, pMapK, DmPp2A-28D, l(3)S029403, sarcoglycan, v-Raf, NK|GPI, l(3)S033903, Migrants and Transients, CG7913, DmERKA, l(1)pole hole, rl/MAPK, Wrd, CRAF, MAP2K, l(3)S042630, non-specific serine/threonine protein kinase activity, pp2A-B', l(2)41Ac, Methodological, l(1)polehole, D-raf, ERK activator kinase activity, experimental procedures, living, Phosphohydrolase, CT34260, dPP2A A, l(3)S075902b, CMD1NN, Sector, dpERk, signaling pathway, wrd, A/PR65, B-Lymphocyte, 35kD dystrophin-associated glycoprotein, Proliferation, serine-specific protein kinase activity, l(3)S066813, Phosphoric, l(3)S027127, SAPK, HIPK2, cytidine 3', B56-2, Migrants, EG:BACH48C10.3, Feedbacks, BB129353, Wee 1-like kinase activity, l(3)S042629, MEK1, MEK2, Bglap-rs1, B56-1, l(3)S063110, LD02456, Sectors, DmelCG14080, glycogen synthase A kinase activity, Effects, dPP2A-B56-1, dPP2A-B56-2, glycogen synthase kinase 3 activity, number, 12559, CG5643, DRaf, Copyrights, protein-containing complex, draf, phosphorylase b kinase kinase activity, EK2-1, l(3)S132907, pyst1, l(3)S069206a, relational shape quality, l(3)S023141a, Gene Products, disease or disorder, Pgi, CG17291, MAM, gamma-SG, ribosomal protein S6 kinase II activity, i234, Enterprises, Technique, D-RAF, D-Raf, l(3)S119908, Erk, ERK, PRKM1, l(3)j11C8, PRKM2, protein-serine kinase activity, l(3)S046918, anatomical systems, lateral shoot, PP2A[B'-1], Longterm, l(3)S088513, Gpi-1r, dPP2A-Balpha, Gpi-1s, ligand, proliferating, MAPK signaling, Phi, STK32, PCBC, Gpi-1t, Phl, dPP2A-C, Long-Term, Worker, Public Enterprises, 5559, BEST:LD02456, Phosphoric Monoester Hydrolase, erk, Study, PP2A[B'-2], DPR65, protein-cysteine kinase activity, l(3)S029110, Hpr kinase activity, rll, Draf, STK26, STK27, p38-2, PP2Ac, Enterprise, ppp2r2c, myelin basic protein kinase activity, Differentiation, l(3)S076415, ATP:protein phosphotransferase (MAPKKK-activated) activity, mitogen-activated protein kinase kinase activity, l(3)S023938, DPR55, CG 7913, DRT, 35 kDa dystrophin-associated glycoprotein, mkp-3, EP3559, raf-1, Proteins, disorders, stress-activated kinase activity, Phosphorylations, MAP-2 kinase activity, function, protein serine kinase activity, MF, Amf, Cell, SGCG, protein phosphokinase activity, PKA, DmelCG5643, native protein, PKC, Public, stress-activated protein kinase activity, mapk2, Long Term Effects, chemical analysis, mapk1, PP2A C, condition, PP2A A, MFS1, background, signalling cascade, AA990557, Mitogen, protein kinase p58 activity, DMKP-3, NK, Differentiations, serine/threonine protein kinase activity, 1300019I03Rik, l(2)02496, CG12559, DMDA1, DmelCG17291, dpERK1, l(2)s5286, l(3)S032303, Dmkp3, Bursa-Equivalent Lymphocyte, Cell Differentiations, l(3)S075110, dsk1, 5'-cyclic monophosphate-responsive protein kinase activity, atypical PKC activity, tws/aar, Longterm Effects, Phytomitogens, plan specification, l(3)S105605, l(1)polehole/draf, Gene Proteins, dpMAPK, ppp2r2b-a, Nomads, sheath of cells, ph, protein serine-threonine kinase activity, SAP kinase activity, Pp2A29B, glycogen synthase kinase activity, MGC130048, c-Raf, l(3)S025913, protein kinase A activity, determination, ERK/MAPK cascade, DmelCG7913, Bursa-Dependent Lymphocytes, Mpk2, p42mapk, protein, l(3)S060804, SR2-1, l(3)S024838, l(3)S025806, Phosphatases, Hydrolase, Techniques, l(3)S045519, diseases, l(3)S043008b, kinase-related transforming protein, Tws, 0318/07, diseases and disorders, PP2, l(3)S031006, mitogen-activated protein kinase activity, l(3)S053011, l(3)S080409, protein aggregate, Gpi-1, mpk1, Effect, human disease, Erk/Map kinase, l(3)s1801, Migrant Worker, pre-mortem, l(3)S049902, Nlk, l(3)S067109b, long, TYPE 2A SERINE/THREONINE PROTEIN PHOSPHATASE, Public Domains, DERK-A, MTS/PP2A, E(sina)7, Craf1, Rl, Raf kinase activity, MP kinase activity, serine kinase activity, DERK, v158, B lymphocyte, Methodological Studies, atypical protein kinase C activity, MAPKKK cascade during sporulation, MKK, R75353, MBP kinase II activity, F20P5.30, Squatters, gamma-sarcoglycan, mitogen-activated S6 kinase activity, protein-aspartyl kinase activity, dERK, GPHYSD2, Long-Term Effects, ER2-6, ATP, single-organism behavior, l(3)S043029, F20P5_30, l(3)S024834a, tw, PP2a 28D, 6430402F14Rik, MAP kinase 2 activity, Papers, Mapk, l(3)S025832, l(3)S022440, SG-gamma, lamina, CG7109, Erk1, ERK1, ERK2, mapk1a, B/PR55, l(3)S101413b, Pp2A-85F, results, M phase-specific cdc2 kinase activity, l(3)S023309, shortened, signaling cascade, l(3)S110008a, mOC-X, mapk1b, MapK, MAPK, Migrant, Workers, serine protein kinase activity, DRaf1, erk2, mapk, BcDNA:LD34343, Domain, l(3)S029701a, l(1)G0475, ptpa, PP2A B', Transphosphorylases, ERKa, phosphorylase B kinase kinase activity, Org, ORG, BcDNA:RE08694, protein glutamyl kinase activity, l(2R)EMS45-39, Draf1, raf1, CAPB, PTPA, DmelCG12559, MAP kinase kinase 7 activity, p38, CG6235, Gpi1-r, Gpi1-s, l(3)S061915, MASS, gamma (35kDa dystrophin-associated glycoprotein), Gpi1-t, Methodological Study, CG33297, DpErk, DpERK, l(3)S066017, l(3)S032708c, ErkA, disease, ERKA, hydroxyalkyl-protein kinase activity, WEE1Hu, l(3)S023206, DMDA, spine, MAPK signalling, epsilon PKC, l(3)S134601a, l(3)S022361, C110, l(3)S061805, short, Hydrolases, pERK, Gpi1s, rafl, Proliferating, other disease, ribosomal S6 protein kinase activity, calcium/phospholipid-dependent protein kinase activity, SGCG_HUMAN, HH19, Procedures, GroupII, experimental, MAPKK1, AI461847, PP2A-29B, NS5, FBN, Gene, Wdb, dPP2A, Monoester Hydrolase, l(3)S075515b, l(3)S111515, CG13383, presence, TYPE, Migrant Workers, protrusion, dPR55, DAGA4, method, l(3)S048507, Proto-oncogene c-RAF, Hek5, ECTOL1, method used in an experiment, 35DAG, Phytomitogen, Studies, serine(threonine) protein kinase activity, SCG3, Phosphotransferase, dB56-2, dB56-1, Raf1, BcDNA:GM05554, T-antigen kinase activity, MKK2, galactosyltransferase-associated kinase activity, PP2A-A, reactivity, MKK4, B'/PR61, B-cell, PP2A-B, l(3)S022205b, methods, PP2A-C, l(3)S146606, DmelCG2845, MKK6, experimental section, MKK7, layer, xp42, Transients, stubby, Nonmigrants, Transphosphorylase, p42 mitogen-activated protein kinase activity, CG18732, ATP:protein phosphotransferase (MAPKK-activated) activity, OCTD, non-neoplastic, Squatter, protein kinase (phosphorylating) activity, signalling pathway, Abstract, Raf-1, l(1)raf, l(3)S024455, disorder, DmERK-A, Long-Term Effect, casein kinase (phosphorylating) activity, axillary shoot, ert1, l(3)S060203, protein complex, Mts, l(3)S023013, prkm2, prkm1, CT39192, l(1)2Fe, medical condition, l(3)S028707, MAP kinase or ERK kinase activity, l(3)S052810, Phosphotransferases, LGMD2C, p38delta, Phosphomonoesterase, count in organism, twitchin kinase activity, 2.7.11.1, Raf/phl, MEK activity, Protein, AP50 kinase activity, MBP kinase I activity, Nomad, WMS2, Data Base, Xp42, threonine-specific protein kinase activity, Phosphoric Monoester, MAPKK, Exhibit, distinct, Kinases, mitogen activated kinase activity, Su(Raf)2B, MAPKK activity, mkp3, phosphoric monoester hydrolase activity, EY2-2, PYST1, l(1)ph, 11-29, introduction, Phosphohydrolases, Protein Gene Products, D-ERK, D830050J10Rik, EPHT3, SCARMD2, SSKS, layer of cells, 2414, 6330556D22Rik, assay, response, RAF, Raf, MKP-3, B-lymphocyte, MAP kinase 1 activity, A-kinase activity, CG2845"],"pubmed_title_synonyms":["Transphosphorylases, Phosphoric Monoester, MAPK signaling., Difference, Kinases, Phosphatase, ERK/MAPK cascade, Different, phosphoric monoester hydrolase activity, Transphosphorylase, Monoester Hydrolase, Robustness, Phosphomonoesterases, Phosphotransferases, Phosphoric Monoester Hydrolase, Phosphohydrolases, Phosphatases, Differential, Phosphomonoesterase, Hydrolase, Phosphohydrolase, MAPKKK cascade during sporulation, MAPK signalling, Phosphoric, Flow, Conflict, Kinase, ATP Phosphotransferases, Analytical Procedure Robustness, Hydrolases, phosphatase, Phosphotransferase, ATP"],"additional_accession":[]},"is_claimable":false,"name":"Sarma2012 - Interaction topologies of MAPK cascade (M2_K2_USEQ)","description":"\n      \n        Sarma2012 - Interaction topologies of MAPK cascade (M2_K2_USEQ)\n        \n          The paper presents the various interaction topologies between the kinases and phosphatases of MAPK cascade. They are represented as M1, M2, M3 and M4. The kinases of the cascades are MKKK, MKK and MK, and Phos1, Phos2 and Phos3 are phosphatases of the system. All three kinases in a M1 type network have specific phosphatases Phos1, Phos2 and Phos3 for the dephosphorylation process. In a M2 type system, kinases MKKK and MKK are dephosphorylated by Phos1 and MK is dephosphorylated by Phos2. The architecture of system like M3 is such that MKKK gets dephosphorylated by Phos1, whereas Phos2 dephosphorylates both MKK and MK. Finally, the MAPK cascade exhibiting more complex design of interaction such as M4 is such that MKKK and MKK are dephosphorylated by Phos1 whereas MKK and MK are dephosphorylated by Phos2. In addition, as it is plausible that the kinases can sequester their respective phosphatases by binding to them, this is considered in the design of the systems (PSEQ-sequestrated system; USEQ-Unsequestrated system). The robustness of different interaction designs of the systems is checked, considering both MichaelisMenten type kinetics (K1) and elementary mass action kinetics (K2). In the living systems, the MAPK cascade transmit both short and long duration signals where short duration signals trigger proliferation and long duration signals trigger cell differentiation. These signal variants are considered to interpret the systems behaviour. It is also tested how the robustness and signal response behaviour of K2 models are affected when K2 assumes quasi steady state (QSS). The combinations of the above variants resulted in 40 models (MODEL1204280001-40). All these 40 models are available from        BioModels Database\n            .        \n        Models that correspond to type M4 with mass-action kinetics K2, in four condition 1) USEQ [        MODEL1204280020\n            - M4_K2_USEQ], 2) PSEQ [        MODEL1204280024\n            - M4_K2_PSEQ], 3) QSS_USEQ [        MODEL1204280036\n            - M4_K2_QSS_USEQ] and 4) QSS_PSEQ [        MODEL1204280040\n            - M4_K2_QSS_PSEQ] are available from the curated branch. The remaining 36 models can be accessed from the non-curated branch.        \n      This model [        MODEL1204280018\n            - M2_K2_USEQ] correspond to type M2 with mass action kinetics K2, in USEQ (Unsequestrated ) condition. This model can accessed from the non-curated branch of        BioModels Database\n            .        \n  \n  \n    This model is described in the article:\n    \n      Different designs of kinase-phosphatase interactions and phosphatase sequestration shapes the robustness and signal flow in the MAPK cascade.\n    \n    Sarma U, Ghosh I.\n    BMC Syst Biol. 2012 Jul 2;6(1):82.\n    Abstract:\n    \n      ABSTRACT:\n\nBACKGROUND: The three layer mitogen activated protein kinase (MAPK) signaling cascade exhibits different designs of interactions between its kinases and phosphatases. While the sequential interactions between the three kinases of the cascade are tightly preserved, the phosphatases of the cascade, such as MKP3 and PP2A, exhibit relatively diverse interactions with their substrate kinases. Additionally, the kinases of the MAPK cascade can also sequester their phosphatases. Thus, each topologically distinct interaction design of kinases and phosphatases could exhibit unique signal processing characteristics, and the presence of phosphatase sequestration may lead to further fine tuning of the propagated signal.\nRESULTS:\n\nWe have built four models of the MAPK cascade, each model with identical kinase-kinase interactions but unique kinases-phosphatases interactions. Our simulations unravelled that MAPK cascade's robustness to external perturbations is a function of nature of interaction between its kinases and phosphatases. The cascade's output robustness was enhanced when phosphatases were sequestrated by their target kinases. We uncovered a novel implicit/hidden negative feedback loop from the phosphatase MKP3 to its upstream kinase Raf-1, in a cascade resembling the B cell MAPK cascade. Notably, strength of the feedback loop was reciprocal to the strength of phosphatases' sequestration and stronger sequestration abolished the feedback loop completely. An experimental method to verify the presence of the feedback loop is also proposed. We further showed, when the models were activated by transient signal, memory (total time taken by the cascade output to reach its unstimulated level after removal of signal) of a cascade was determined by the specific designs of interaction among its kinases and phosphatases.\nCONCLUSIONS:\n\nDifferences in interaction designs among the kinases and phosphatases can differentially shape the robustness and signal response behaviour of the MAPK cascade and phosphatase sequestration dramatically enhances the robustness to perturbations in each of the cascade. An implicit negative feedback loop was uncovered from our analysis and we found that strength of the negative feedback loop is reciprocally related to the strength of phosphatase sequestration. Duration of output phosphorylation in response to a transient signal was also found to be determined by the individual cascade's kinase-phosphatase interaction design.\n    \n  \n  \n    This model is hosted on        BioModels Database\n            and identified by:        MODEL1204280018\n            .        \n  To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. PMID:        20587024\n            .        \n\n  To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to [CC0 Public Domain Dedication>http://creativecommons.org/publicdomain/zero/1.0/] for more information.\n\n\n","dates":{"last_modification":"2012-11-23","publication":"2005-01-01","submission":"2012-04-28"},"accession":"MODEL1204280018","cross_references":{"pubmed":["22748295"],"biomodels__db":["MODEL1204280018"],"go":["GO:0000165"],"taxonomy":["10090"]}}