BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048.pdfhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048.svghttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048-biopax2.owlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048-biopax3.owlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048_url.xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048_urn.xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048.xpphttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048.scihttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048.pnghttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048.vcmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000048?filename=BIOMD0000000048.mprimaryOK2000010Lu LiManually curatedL2V1https://www.ebi.ac.uk/biomodels/BIOMD0000000048falseBioModelsModelsSBMLKholodenko1999 EGFR signaling1999MODEL6624193277Kholodenko BN, Demin OV, Moehren G, Hoek JBKholodenko BN10514507, During the past decade, our knowledge of molecular mechanisms involved in growth factor signaling has proliferated almost explosively. However, the kinetics and control of information transfer through signaling networks remain poorly understood. This paper combines experimental kinetic analysis and computational modeling of the short term pattern of cellular responses to epidermal growth factor (EGF) in isolated hepatocytes. The experimental data show transient tyrosine phosphorylation of the EGF receptor (EGFR) and transient or sustained response patterns in multiple signaling proteins targeted by EGFR. Transient responses exhibit pronounced maxima, reached within 15-30 s of EGF stimulation and followed by a decline to relatively low (quasi-steady-state) levels. In contrast to earlier suggestions, we demonstrate that the experimentally observed transients can be accounted for without requiring receptor-mediated activation of specific tyrosine phosphatases, following EGF stimulation. The kinetic model predicts how the cellular response is controlled by the relative levels and activity states of signaling proteins and under what conditions activation patterns are transient or sustained. EGFR signaling patterns appear to be robust with respect to variations in many elemental rate constants within the range of experimentally measured values. On the other hand, we specify which changes in the kinetic scheme, rate constants, and total amounts of molecular factors involved are incompatible with the experimentally observed kinetics of signal transfer. Quantitation of signaling network responses to growth factors allows us to assess how cells process information controlling their growth and differentiation.. null, 274. Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. Boris.Kholodenko@mail.tju.edululi@ebi.ac.ukEMBL-EBIBIOMD0000000048During the past decade, our knowledge of molecular mechanisms involved in growth factor signaling has proliferated almost explosively. However, the kinetics and control of information transfer through signaling networks remain poorly understood. This paper combines experimental kinetic analysis and computational modeling of the short term pattern of cellular responses to epidermal growth factor (EGF) in isolated hepatocytes. The experimental data show transient tyrosine phosphorylation of the EGF receptor (EGFR) and transient or sustained response patterns in multiple signaling proteins targeted by EGFR. Transient responses exhibit pronounced maxima, reached within 15-30 s of EGF stimulation and followed by a decline to relatively low (quasi-steady-state) levels. In contrast to earlier suggestions, we demonstrate that the experimentally observed transients can be accounted for without requiring receptor-mediated activation of specific tyrosine phosphatases, following EGF stimulation. The kinetic model predicts how the cellular response is controlled by the relative levels and activity states of signaling proteins and under what conditions activation patterns are transient or sustained. EGFR signaling patterns appear to be robust with respect to variations in many elemental rate constants within the range of experimentally measured values. On the other hand, we specify which changes in the kinetic scheme, rate constants, and total amounts of molecular factors involved are incompatible with the experimentally observed kinetics of signal transfer. Quantitation of signaling network responses to growth factors allows us to assess how cells process information controlling their growth and differentiation.Quantification of short term signaling by the epidermal growth factor receptor.Kholodenko B N BN, Demin O V OV, Moehren G G, Hoek J B JBDER/faint little ball, projections, extent, para Tyrosine, Public Sectors, Activity, determination, PLXN2, CFD1, postnatal development, Elp-B1, der, Elp-1, TGF-alpha receptor binding, Hepatocyte, Errb1, growth and development, phosphorylation, CD332, PIG61, Personal, forelimb autopod, Human Urinary Gastric Inhibitor, Hepatic Cell, epidermal growth factor-activated receptor activity, AI552599, responsivity, PAST, Public Enterprise, d-egf-r, me75, Migrant Worker, reference sample, HAND, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, Public Domains, Nonmigrant, bHLHa28, Growth Factor-Urogastrone, proteins, Y, Transient, D17Mit170, flb, T1, foot, hand, transforming growth factor alpha receptor binding, BEK, signaling process, Tyr, papilla, Squatters, 9030024J15Rik, D-EGFR, HPAST1, mKIAA0463, NISBD2, single organism signaling, DER1, ratio, forefoot of quadruped, PlexA2, anatomical protrusion, Elp, Papers, Wa5, l(2)09261, completeness, DEgfr, 2-Amino-3-(p-hydroxyphenyl)propionic acid, lamina, flanges, terminal segment of free upper limb, para-Tyrosine, Tl3, Tl2, CG10079, Tyrosine, shortened, Hepatic Cells, torpedo/egfr, JWS, AW457381, paw, wa2, Public Domain, beta Urogastrone, Migrant, shelf, Suggestions, Domains, Workers, Urogastrone, tyrosine, Migrants and Transients, activation, Domain, egfr, Jackson-Weiss syndrome, Epistemology, figures, HD-33, El, growth pattern, non-developmental growth, EGFR, DER/EGFR, EGfr, EgfR, shelves, dEgfr, BBDS, L-isomer, Dignity, proportionality, Epidermal growth factor, DER flb, rate, Torpedo/Egfr, PAST1, projection, ridge, TK25, Degfr, midfacial hypoplasia, experimental procedures, L isomer, Sector, spine, DEGFR, hand region, l(2)57DEFa, l(2)05351, Cells, fore paw, dEGFR, Migrants, L-Tyrosine, DmHD-33, short, forefoot, Plxn2, TGFalpha receptor binding, TK14, OCT, receptor tyrosine-protein kinase erbB-1, forelimb autopodium, biological signaling, EGF receptor binding, Sectors, Respect, D-Egf, proto-oncogene c-ErbB-1, experimental, K-SAM, KGFR, H-PAST, lamellae, C-erb, number, mor1, Gene, Copyrights, mENA, EK2-6, process of organ, presence, Migrant Workers, protrusion, lamella, beta-Urogastrone, AI790464, Egfr, c-erbB, EGFr, Gene Products, CG18144, EGF receptor activity, torpedo/Egfr, TOP, Growth Factor, Egf-r, CEK3, Low, Enterprises, epidermal growth factor, reactivity, EGF-R, proportion, transforming growth factor alpha receptor ligand, methods, pattern, epidermal growth factor receptor ligand, URG, distribution, experimental section, Transients, dHand, EGFR binding, stubby, top, Nonmigrants, Torpedo/DER, 2810428A13Rik, ridges, Worker, Public Enterprises, ECT1, Dhand, top/flb, Squatter, Epidermal Growth Factor-Urogastrone, Abstract, hand-C, HOMG4, L Tyrosine, l(2)57EFa, transient structure, Personal Respect, EGF receptor ligand, BFR-1, dHAND, Hepatic, l(2)57Ea, Tyrosin, Enterprise, laminae, Controlled, Elp-B1RB1, and foot abnormalities, Controlling, data, cou, TGF-alpha receptor activity, ERBB, dEGFR1, craniosynostosis-midfacial hypoplasia-foot abnormalities syndrome, anatomical process, Proteins, Phosphorylations, AA589422, Cell, development, count in organism, Lr, transforming growth factor alpha, epidermal growth factor receptor activity, DmelCG10079, tirosina, Public, fore-paw, chemical analysis, Protein, Nomad, phosphorylation enrichment, DER/top, forefeet, flange, organ process, Data Base, Exhibit, top/DER, DmelCG18144, postnatal growth, ERBB1, Craniosynostosis - midfacial hypoplasia - foot abnormalities, wa-2, signalling, Protein Gene Products, Hands, craniosynostosis, Gene Proteins, processes, process, Egf, EGF, EFG-R, signalling process, Epidermal, Errp, fore foot, Erbb, Nomads, Der, DER, Bra, quotient, forepaw, processus, Public., transforming growth factor-alpha receptor activity, assay, response, quantitative, growth, General activity, DER/torpedo, HER1, presence or absence in organismDER/faint little ball, Elp-B1RB1, signalling., receptor tyrosine-protein kinase erbB-1, biological signaling, Elp, D-Egf, proto-oncogene c-ErbB-1, Wa5, l(2)09261, TGF-alpha receptor activity, ERBB, C-erb, dEGFR1, DEgfr, Elp-B1, der, Elp-1, mor1, Errb1, mENA, EK2-6, CG10079, PIG61, torpedo/egfr, epidermal growth factor receptor activity, wa2, DmelCG10079, epidermal growth factor-activated receptor activity, AI552599, Egfr, c-erbB, EGFr, EGF receptor activity, torpedo/Egfr, TOP, Egf-r, DER/top, d-egf-r, egfr, EGF-R, HD-33, El, top/DER, EGFR, DER/EGFR, EGfr, EgfR, dEgfr, DER flb, top, Torpedo/DER, ERBB1, wa-2, Torpedo/Egfr, flb, top/flb, Degfr, Egf, EFG-R, signalling process, Errp, l(2)57EFa, Erbb, DEGFR, signaling process, l(2)57DEFa, l(2)05351, Der, DER, 9030024J15Rik, D-EGFR, dEGFR, l(2)57Ea, transforming growth factor-alpha receptor activity, DmHD-33, DER/torpedo, HER1, NISBD2, single organism signaling, DER1ter, shortened, receptor tyrosine-protein kinase erbB-1, DmelCG4216, biological signaling, signalling process, proto-oncogene c-ErbB-1, Bsg75C, Term, signaling process, ERBB, EGFR., CG4216, stubby, ERBB1, short, HER1, single organism signaling, signallingDER/faint little ball, projections, para Tyrosine, postnatal development., Activity, determination, postnatal development, Elp-B1, der, Elp-1, TGF-alpha receptor binding, Hepatocyte, Errb1, growth and development, sci, phosphorylation, ter, PIG61, Personal, forelimb autopod, Human Urinary Gastric Inhibitor, Hepatic Cell, epidermal growth factor-activated receptor activity, AI552599, responsivity, HOW, How, PAST, d-egf-r, l(3)j5D5, 24B, me75, Migrant Worker, reference sample, HAND, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, Nonmigrant, stru, bHLHa28, Growth Factor-Urogastrone, proteins, l(3)S053606, Y, Transient, CG10293, D17Mit170, flb, T1, foot, hand, l(3)j5B5, transforming growth factor alpha receptor binding, Bsg75C, signaling process, Tyr, papilla, Squatters, 9030024J15Rik, D-EGFR, HPAST1, NISBD2, single organism signaling, DER1, ratio, forefoot of quadruped, 0904/17, anatomical protrusion, Papers, Elp, l(2)09261, Wa5, DEgfr, 2-Amino-3-(p-hydroxyphenyl)propionic acid, lamina, flanges, terminal segment of free upper limb, para-Tyrosine, Tl3, Tl2, CG10079, Tyrosine, shortened, Hepatic Cells, torpedo/egfr, paw, wa2, Term, SZ1, beta Urogastrone, Migrant, shelf, Suggestions, Workers, Urogastrone, tyrosine, Migrants and Transients, activation, egfr, Epistemology, HD-33, El, growth pattern, non-developmental growth, DER/EGFR, EGFR, EGfr, EgfR, shelves, dEgfr, L-isomer, Dignity, proportionality, Epidermal growth factor, DER flb, rate, PAST1, Torpedo/Egfr, projection, ridge, experimental procedures, Degfr, L isomer, spine, DEGFR, hand region, l(2)57DEFa, l(2)05351, Cells, fore paw, dEGFR, Migrants, anon-EST:Liang-2.39, L-Tyrosine, DmHD-33, short, forefoot, TGFalpha receptor binding, receptor tyrosine-protein kinase erbB-1, forelimb autopodium, biological signaling, EGF receptor binding, Respect, D-Egf, proto-oncogene c-ErbB-1, experimental, H-PAST, lamellae, C-erb, P62, mor1, Gene, mENA, EK2-6, process of organ, Migrant Workers, protrusion, lamella, beta-Urogastrone, AI790464, c-erbB, EGFr, Egfr, Gene Products, CG18144, torpedo/Egfr, EGF receptor activity, TOP, Growth Factor, Egf-r, Low, epidermal growth factor, reactivity, EGF-R, proportion, transforming growth factor alpha receptor ligand, methods, pattern, l(3)s2612, epidermal growth factor receptor ligand, URG, distribution, experimental section, Transients, dHand, EGFR binding, stubby, top, Nonmigrants, Torpedo/DER, ridges, Worker, Dhand, top/flb, Squatter, Epidermal Growth Factor-Urogastrone, DmelCG4216, hand-C, HOMG4, L Tyrosine, l(2)57EFa, transient structure, Personal Respect, EGF receptor ligand, DmelCG10293, dHAND, Hepatic, l(2)57Ea, Tyrosin, laminae, Controlled, Elp-B1RB1, Controlling, data, cou, TGF-alpha receptor activity, clone 2.39, dEGFR1, ERBB, anatomical process, Proteins, Phosphorylations, qkr, l(3)S090417, Cell, development, Lr, transforming growth factor alpha, epidermal growth factor receptor activity, DmelCG10079, tirosina, fore-paw, KH93F, chemical analysis, Protein, Nomad, phosphorylation enrichment, DER/top, forefeet, flange, organ process, who, Exhibit, top/DER, DmelCG18144, postnatal growth, CG4216, ERBB1, Who/How, wa-2, signalling, Protein Gene Products, Hands, Gene Proteins, processes, process, EGF, Egf, EFG-R, signalling process, Epidermal, Errp, fore foot, Erbb, Nomads, Der, DER, Bra, quotient, qkr[93F], forepaw, processus, assay, transforming growth factor-alpha receptor activity, response, growth, General activity, DER/torpedo, HER11falseKholodenko1999 - EGFR signaling Kholodenko1999 - EGFR signaling This model has been generated by the JWS Online project by Jacky Snoep using PySCeS Run this model online at http://jjj.biochem.sun.ac.za To cite JWS Online please refer to: Olivier, B.G. and Snoep, J.L. (2004) Web-based modelling using JWS Online , Bioinformatics, 20:2143-2144 This model is described in the article: Quantification of short term signaling by the epidermal growth factor receptor. Kholodenko BN, Demin OV, Moehren G, Hoek JB J. Biol. Chem. 1999 Oct; 274(42): 30169-30181 Abstract: During the past decade, our knowledge of molecular mechanisms involved in growth factor signaling has proliferated almost explosively. However, the kinetics and control of information transfer through signaling networks remain poorly understood. This paper combines experimental kinetic analysis and computational modeling of the short term pattern of cellular responses to epidermal growth factor (EGF) in isolated hepatocytes. The experimental data show transient tyrosine phosphorylation of the EGF receptor (EGFR) and transient or sustained response patterns in multiple signaling proteins targeted by EGFR. Transient responses exhibit pronounced maxima, reached within 15-30 s of EGF stimulation and followed by a decline to relatively low (quasi-steady-state) levels. In contrast to earlier suggestions, we demonstrate that the experimentally observed transients can be accounted for without requiring receptor-mediated activation of specific tyrosine phosphatases, following EGF stimulation. The kinetic model predicts how the cellular response is controlled by the relative levels and activity states of signaling proteins and under what conditions activation patterns are transient or sustained. EGFR signaling patterns appear to be robust with respect to variations in many elemental rate constants within the range of experimentally measured values. On the other hand, we specify which changes in the kinetic scheme, rate constants, and total amounts of molecular factors involved are incompatible with the experimentally observed kinetics of signal transfer. Quantitation of signaling network responses to growth factors allows us to assess how cells process information controlling their growth and differentiation. The model correctly reproduces all the figures from the paper. The curation has been done using SBMLodeSolver. This model is hosted on BioModels Database and identified by: BIOMD0000000048 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . 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 for more information. 2014-02-142005-11-232005-12-05BIOMD00000000482__7__1__373__1__3__16MODEL6624193277BIOMD000000004810514507GO:0007173GO:0005737GO:0048408GO:0005154GO:0045741GO:0046983GO:0006468GO:0004716GO:0006470GO:0051425GO:0042169GO:0017124GO:0005070GO:0005068GO:003084510116P07522Q9QX70P10686P24135P62994Q9Z1I1Q5M824IPR001192