{"database":"BioModels","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Txt":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=curation_notes.txt"],"Pdf":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173.pdf"],"Svg":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173.svg"],"Owl":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173-biopax3.owl","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173-biopax2.owl"],"Xml":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=manifest.xml","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173_url.xml"],"Other":["https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=metadata.rdf","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=curation_image.png","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173.png","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173-octave.m","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173_url.sedml","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173.ode","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173.m","https://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000173?filename=BIOMD0000000173-matlab.m"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"submitter":["Bernhard Schmierer"],"curationStatus":["Manually curated"],"modellingApproach":["ordinary differential equation model"],"levelVersion":["L2V1"],"full_dataset_link":["https://www.ebi.ac.uk/biomodels/BIOMD0000000173"],"publication_pubmed":["18443295"],"isPrivate":["false"],"repository":["BioModels"],"modelFormat":["SBML"],"omics_type":["Models"],"tokenised_name":["Schmierer 2008 Smad Tgfb"],"publication_year":["2008"],"submissionId":["MODEL0451870146"],"publication_authors":["Bernhard Schmierer, Alexander L Tournier, Paul A Bates, Caroline S Hill"],"first_author":["Bernhard Schmierer"],"publication":["18443295,\n                            TGF-beta-induced Smad signal transduction from the membrane into the nucleus is not linear and unidirectional, but rather a dynamic network that couples Smad phosphorylation and dephosphorylation through continuous nucleocytoplasmic shuttling of Smads. To understand the quantitative behavior of this network, we have developed a tightly constrained computational model, exploiting the interplay between mathematical modeling and experimental strategies. The model simultaneously reproduces four distinct datasets with excellent accuracy and provides mechanistic insights into how the network operates. We use the model to make predictions about the outcome of fluorescence recovery after photobleaching experiments and the behavior of a functionally impaired Smad2 mutant, which we then verify experimentally. Successful model performance strongly supports the hypothesis of a dynamic maintenance of Smad nuclear accumulation during active signaling. The presented work establishes Smad nucleocytoplasmic shuttling as a dynamic network that flexibly transmits quantitative features of the extracellular TGF-beta signal, such as its duration and intensity, into the nucleus.. 18, 105.\n                            Developmental Signalling Laboratory and Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom."],"submitter_mail":["Bernhard.Schmierer@ymail.com"],"submitter_affiliation":["Developmental Signalling Lab, Cancer Research UK London Research Institute"],"publicationId":["BIOMD0000000173"],"pubmed_abstract":["TGF-beta-induced Smad signal transduction from the membrane into the nucleus is not linear and unidirectional, but rather a dynamic network that couples Smad phosphorylation and dephosphorylation through continuous nucleocytoplasmic shuttling of Smads. To understand the quantitative behavior of this network, we have developed a tightly constrained computational model, exploiting the interplay between mathematical modeling and experimental strategies. The model simultaneously reproduces four distinct datasets with excellent accuracy and provides mechanistic insights into how the network operates. We use the model to make predictions about the outcome of fluorescence recovery after photobleaching experiments and the behavior of a functionally impaired Smad2 mutant, which we then verify experimentally. Successful model performance strongly supports the hypothesis of a dynamic maintenance of Smad nuclear accumulation during active signaling. The presented work establishes Smad nucleocytoplasmic shuttling as a dynamic network that flexibly transmits quantitative features of the extracellular TGF-beta signal, such as its duration and intensity, into the nucleus."],"pubmed_title":["Mathematical modeling identifies Smad nucleocytoplasmic shuttling as a dynamic signal-interpreting system."],"pubmed_authors":["Schmierer Bernhard B, Tournier Alexander L AL, Bates Paul A PA, Hill Caroline S CS"],"pubmed_abstract_synonyms":["Networks, Signal Transductions, Presented, SMAD family member 2, smad-2, Approximate, Feature, Success, ted, Verified, let it be made, AtrII, Act-r, sci, DPP-C, apg, fiat, Verify, phosphorylation, TGFbeta, Milk, Milk Growth Factor, Receptor Mediated Signal Transduction, Hin-d, Milk Growth, Membrane Tissues, DmelCG9885, Make, Presenting, DmelCG7904, P-mad, horsetail nucleus, HOW, How, Cell Signaling, Consortium, Smad, l(3)j5D5, Dm-DPP, signal transduction by protein phosphorylation, 24B, hSMAD2, Centers, MADH2, ced, tgf-beta, M(2)23AB, horsetail nucleus., Maker, JV18-1, P-Mad, membrane region, result, Tissue, JV18, stru, Pathways, l(3)S053606, tgfb, CG10293, Computational, dMAD, dMad, l(3)j5B5, Had, Manufacturer Name, p-Mad, Computational Technique, Presentation, Network Interface, Mothers against DPP homolog 2, atrII, Signal Transduction Pathways, Transductions, Outcome, Has, Atr, single organism signaling, single-organism behavior, 7120426M23Rik, Membrane Tissue, 0904/17, Pathway, and Consortia, Process, statistics and numerical data, Punt, TGF-beta, signal transduction by conformational transition, Tg, integral to membrane, CG9885, dephosphorylation, CG7904, signal transduction by trans-phosphorylation, Acceptance Processes, signaling cascade, Acceptance Process, Induction, Atr88CD, SZ1, dSMAD2, Atr-II, l(2)22Fa, PUNT, l(1)G0348, DSMAD2, About, cell nucleus, numerical data, XSmad2, l(3)10460, Mutant, dSmad2, Transduction, hMAD-2, l(2)k17036, shv, PMad, Mathematics, mMad2, Mad-related protein 2, Modeling, System, FRAPs (Fluorescence Recovery After Photobleaching), Platelet Transforming Growth Factor, Network Device, En(vvl), Features, Present, pSmad, CG12399, dsmad2, experimental procedures, signaling pathway, Put, anon-EST:Liang-2.39, pMAD, pMad, Induced, nucleocytoplasmic shuttling, Signal Transduction Systems, ho, pun, experimental, MADR2, Processes, Math, P62, M(2)LS1, Computed, Consortium or Network, MANUF, TGF-beta5, Receptor-Mediated, number, Bone-Derived Transforming Growth Factor, Signal Transduction System, tmp, Network, Constrain, presence, Bone Derived Transforming Growth Factor, Inducible, ft., tgfbeta, Signal Transduction, 2/23, utilization, integral component of membrane, MAD, SMAD 2, Growth Factor, CG2262, tgfb5, Performance, NCI Consortium or Network, DSmad2, Mat, Dpp, DPP, methods, l(3)s2612, dlhC, Tissues, Computing, experimental section, Smad-2, Fluorescence Photobleaching Recovery, mad, Inducing, Signal, smad2, Signal Pathways, Madr2, Maintenances, Signal Transduction Pathway, outcome, E(zen)2, blk, SMAD2, BMP, signalling pathway, MAD homolog 2, l(2)k00237, Mathematical, Verification, MANUFACTURER, DmelCG10293, Smad1, region of membrane, Smad2, signal transduction by cis-phosphorylation, Approximately, Characteristics, Behaviors, Signal Pathway, Possess, DmelCG2262, l(3)j5A5, membrane, use, Tgf-r, TGF-b, clone 2.39, Result, Madh2, Phosphorylations, Receptor-Mediated Signal Transductions, Constrained, Excellent, Factor, Manufacturer, qkr, lap, l(3)S090417, verification, count in organism, Characteristic, Have, Receptor-Mediated Signal Transduction, KH93F, Successful, Systems, whole membrane, FRAP (Fluorescence Recovery After Photobleaching), Nuclear, Computation, Induce, Sad, signalling cascade, who, Acceptance, transforming growth factor beta, transmembrane, distinct, l(2)10638, nucleus of neuraxis, Who/How, sad, Membrane, Manufacturing, extracellular, l(2)K00237, SMOX, DmelCG12399, c28, signalling process, TGF-B, qkr[93F], dpd1, smox, STK-C, hypothesis"],"description_synonyms":["activated cell autonomous cell death, IPP2A2, SMAD family member 4, SMAD family member 2, smad-2, Activity, alphaPS2, Laboratory, AUTSX5, ted, d21s21, NOVH, MA-3, CCN3, QM, 5730420M11Rik, Ad4h, Alg3, Alg2, BC031509, horsetail nucleus, SEC, hp1.a, madh4, CG3751, Isonymies, alpha2Int, Research Activity, xp1, Laboratory Research, phosphate starvation-induced gene 2, BcDNA:RE59324, fs(1)M104, PIST, Priorities, hSMAD2, MADH2, Presenilin-2, hSMAD4, SET, MADH4, XSmad4alpha, TAF-I, tff1, Paul, JV18-1, HOIP, sec, JV18, AI844555, xP1, free, DEPP, DmelCG4299, Rubberplants, IBP-9, IGAAD, set, DmelCG9623, activated T cell apoptosis, anon-EST:Posey121, Mothers against DPP homolog 4, acidos nucleicos, DmelCG10574, Rubberplant, PAUL, Fseg, Mothers against DPP homolog 2, Deletion target in pancreatic carcinoma 4 homolog, AD4, Research Priority, NOVh, time point, phapii, 7120426M23Rik, l(3)12m-137, pnr-2, DmelCG3751, Papers, bcei, 6.3.2.-, PS2, ps2, Name, StF-IT-1, Research Priorities, pNR-2, results, aPS2, Fasting-induced gene protein, CT27194, Isonymy, dSMAD2, nucleic acids, l(1)G0348, DSMAD2, pS2, XSmad2, cell nucleus, NOV, dSmad2, END, BCEI, dSmad4, PlexA1, Nucleic., GOPC1, hMAD-2, Research and Development, Acid, figures, Plxn1, ATPS2, HLA-DR-associated protein II, DI-2, mMad2, Mad-related protein 2, PS-2, Xsmad4, I-2Dm, nov, CG9623, CG4299, Bcei, mKIAA4053, dsmad2, fs(1)Y[b], Nucleic, I-2PP1, Activities, AW743858, TAF-IBETA, C130088N23Rik, JIP, Cytosols, TAF-Ibeta, PLXN1, Acids, DXS648E, PSalpha2, i2pp2a, nucleocytoplasmic shuttling, F3N23.21, DmelCG1775, YB, MADR2, CMD1V, DBA3, jip, number, tmp, Copyrights, hps2, 2210402P09Rik, presence, PHAPII, in, acides nucleiques, Publication, Yb, SMAD 4, Figs, l(3)SG36, SMAD 2, CG2262, Rp S24, MYHRS, CG2706, If, DSmad2, F3N23_21, T6K12_14, DmelCG7615, anatomical systems, medea, alpha[[PS2]], Research, Smad-2, Selb, ipp2a2, smad4, smad2, l(2)SH2053, 2pp2a, IGFBP9, Madr2, integrin, E(zen)3, CG10574, SMAD2, SMAD4, Kiaa4053, MAD homolog 2, p1-a, HPS2, 2PP2A, MAD homolog 4, alphaPS2C, taf-ibeta, L10, dSET, dSet, PS 2, Smad2, AL033293, Smad4, species, Development and Research, xp1-L, l(2)SH2 2053, HHT1, STM2, Decidual protein induced by progesterone, DmelCG2262, Edg, acide nucleique, D21S21, DmelCG2706, Flj10111, Madh2, mFLJ00217, igaad, dpc4, DXS648, l(3)11m-254, ALG-3, Madh4, D18Wsu70e, HOIL-1-interacting protein, group, F6K5_3, count in organism, secret agent, Priority, HP1.A, AV299538, I-2PP2A, IGFBP-9, Psnl2, Nucleic Acid, MED, Dm I-2, I2PP2A, Research Activities, CAL, F6K5.3, NA, xsmad4a, Putative Ariadne-like ubiquitin ligase, Sad, CG1775, Data Base, T6K12.14, p1, AD3L, alg-2, Nukleinsaeure, ensemble, RING finger protein 31, med, S24, nucleus of neuraxis, sad, acido nucleico, l(3)SG70, ACAD, dJ94G16.2, inf, dSET/TAF-Ibeta, 2610030F17Rik, FIG, Fig, SMOX, Deletion target in pancreatic carcinoma 4, concentration, Nukleinsaeuren, EG:95B7.8, CG7615, PS2alpha, alpha[[PS2(ms8)]], 2600013D04Rik, smox, ORW1, AA407739, l(3)XIIm137, DPC4"],"pubmed_title_synonyms":["nucleocytoplasmic shuttling, Mat, PMad, Mathematics, Math, Modeling, P-Mad, mad, En(vvl), apg, pSmad, CG12399, E(zen)2, dMAD, dMad, l(2)K00237, l(2)k00237, DmelCG12399, c28, 2/23, Mathematical, p-Mad, P-mad, Smad1, MAD, pMAD, pMad, anatomical systems., Smad"],"additional_accession":[]},"is_claimable":false,"name":"Schmierer_2008_Smad_Tgfb","description":"\n      \n        \n        \n           This sbml file describes the RECI model from:\n      \n          \n          \n      \n          \n          \n          \n\t  \"Mathematical modeling identifies Smad nucleocytoplasmic shuttling as a dynamic signal-interpreting system\" by Bernhard Schmierer, Alexander L. Tournier, Paul A. Bates and Caroline S. Hill, Proc Natl Acad Sci U S A. 2008 May 6;105(18):6608-13.\n      \n          \n          \n      \n          \n          \n          \n\t  All parameter and species names are as in Figure S3 of the original publication. The original model was done in copasi.\n      \n          \n          \n      \n          \n          \n          \nSB-431542 addition to a concentration of 10000 nM is set at 2700 sec. The initial concentration of SB, the time point of addition and the final concentration can be set by altering the parameters \n      \n          \n          \n      \n          \n          \n          SB_0, \n      \n          \n          \n      \n          \n          \n          t_SB and \n      \n          \n          \n      \n          \n          \n          SB_end.\n      \n          \n          \n      \n          \n          \n            \nThis model file has been used to reproduce Figures 2D and 5A from the research paper using SBMLodesolver. To get the results for the figures, sum the corresponding concentrations:\n      \n          \n          \n      \n          \n          \n          \nfig 2D: nuclear EGFP-Smad2 = G_n + pG_n + G2_n + G4_n + 2* GG_n\n      \n          \n          \n      \n          \n          \n          \nfig 5A (either n or c for nucleus or cytosol):\n      \n          \n          \n      \n          \n          \n          \nmonomeric Smad2 = S2_n/c + G_n/c\n      \n          \n          \n      \n          \n          \n          \nmonomeric P-Smad2 = pS2_n/c + pG_n/c\n      \n          \n          \n      \n          \n          \n          \nSmad2/Smad4 complexes = S24_n/c + G4_n/c\n      \n          \n          \n      \n          \n          \n          \nSmad2/Smad2 complexes = S22_n/c + G2_n/c + GG_n/c\n      \n          \n          \n      \n          \n          \n          \n          This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team.\n          \n          \n          For more information see the \n          \n          \n          terms of use.\n          \n          \n          To cite BioModels Database, please use \n          \n          \n           Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.\n        \n      \n    \n  ","dates":{"last_modification":"2024-08-21","publication":"2024-09-02","submission":"2008-06-04"},"accession":"BIOMD0000000173","cross_references":{"ec-code":["3.1.3.16","2.7.11.30"],"kegg__pathway":["hsa04350"],"pubmed":["18443295"],"biomodels__db":["MODEL0451870146","BIOMD0000000173"],"go":["GO:0043234","GO:0007179","GO:0005634","GO:0005737","GO:0004721","GO:0030291","GO:0006913","GO:0004675","GO:0006461","GO:0004722","GO:0005160","GO:0030512"],"kegg__compound":["C00562"],"taxonomy":["9606"],"uniprot":["Q13485","Q15796","P35813","P01137","P61812","P10600","Q8NER5","P36897","Q5T7S2","P37173"],"interpro":["IPR000786"]}}