Cell CollectiveModelsTomas Helikarhttps://cellcollective.org/#2309/egfr-&-erbb-signaling56.66521SBML1Cell Collectivehttps://cellcollective.org/#2309:1/egfr-&-erbb-signalingThe epidermal growth factor receptor (EGFR) signaling pathway is probably the best-studied receptor system in mammalian cells, and it also has become a popular example for employing mathematical modeling to cellular signaling networks. Dynamic models have the highest explanatory and predictive potential; however, the lack of kinetic information restricts current models of EGFR signaling to smaller sub-networks. This work aims to provide a large-scale qualitative model that comprises the main and also the side routes of EGFR/ErbB signaling and that still enables one to derive important functional properties and predictions. Using a recently introduced logical modeling framework, we first examined general topological properties and the qualitative stimulus-response behavior of the network. With species equivalence classes, we introduce a new technique for logical networks that reveals sets of nodes strongly coupled in their behavior. We also analyzed a model variant which explicitly accounts for uncertainties regarding the logical combination of signals in the model. The predictive power of this model is still high, indicating highly redundant sub-structures in the network. Finally, one key advance of this work is the introduction of new techniques for assessing high-throughput data with logical models (and their underlying interaction graph). By employing these techniques for phospho-proteomic data from primary hepatocytes and the HepG2 cell line, we demonstrate that our approach enables one to uncover inconsistencies between experimental results and our current qualitative knowledge and to generate new hypotheses and conclusions. Our results strongly suggest that the Rac/Cdc42 induced p38 and JNK cascades are independent of PI3K in both primary hepatocytes and HepG2. Furthermore, we detected that the activation of JNK in response to neuregulin follows a PI3K-dependent signaling pathway.The logic of EGFR/ErbB signaling: theoretical properties and analysis of high-throughput data.Samaga Regina R, Saez-Rodriguez Julio J, Alexopoulos Leonidas G LG, Sorger Peter K PK, Klamt Steffen SRac GTPase, Urogastrone Receptor, dmBest1, PRKBA, extracellular signal-regulated kinase activity, GrpL, Akt/PKB, GRPL, pp44mapk, Growth factor receptor-binding protein, SAPKa, dP60, CRKII, Vps34, acetylglucosaminyltransferase-like protein, D-Rac1, HepG2 cell, D-Rac2, DAKT1/PKB, NURF38, DmCDC42, Elp-B1, der, Receptors, Elp-1, Errb1, rac, BcDNA:LD15217, AKT1, p38-alpha, VPS34, 11621, DmelCG6264, Epidermal Growth Factor Receptor Family Protein, p38MAPK, p38a, PIG61, p38ALPHA, Hog, PI-3 kinase, p110-alpha, ErbB-1, Personal, DmelCG8556, LeMPK3, Rac-2, Rac-1, DmelCG12298, epidermal growth factor-activated receptor activity, hnRNP A2/B1, p44mpk, responsivity, Dp38, SCRAMBLED, SAPK1, myd, SAPK2, Mpk34C, JNK-46, p38B, p38A, Dp60, mapk14a, like-acetylglucosaminyltransferase, pp42, DBSK/JNK, Junk, PI3K_59F, hrp40, plant peltate hair, Mbp-1, hnRNP36, PI3-kinase activity, Epidermal Growth Factor Receptor, EGFR family signaling pathway, Hrb87Fa, Dm p38b, Epidermal Growth Factor Receptor Kinase, PI3Kgamma, flb, HepG2 Cell, RacPK, Hrb85CD, Social, MCAP, hrp36, Grf40, TGF-alpha, Smurf, dMKK3, PI3K 68D, 9030024J15Rik, Social Power, GRBLG, CG4943, ESTS:186F5S, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, single organism signaling, Power, DmMPK2, dVps34, dRac1, Elp, EGF Receptors, DEgfr, 6.3.2.-, dJNK, rea, csbp, STRUBBELIG, ERK-2, CG4634, p50alpha, PMK-2, Lack, PMK-1, CG2699, DmelCG5373, signal transduction by trans-phosphorylation, Acceptance Processes, Hrb87f, PMK-3, CSBP, torpedo/egfr, DmIKKgamma, AKT/PKB, GTPase Rac1, C530050K14, Double ring-finger protein, dIKK, mKIAA0609, type-1 PI3K, p-Akt, D-MPK2, GRAP-2, TU15B, Urogastrone, activation, egfr, fg, DmelCG5475, CG11621, D-cdc42, Mek3, MEK3, DMEK3, HD-33, El, DmRAC2, DmRAC1, DER/EGFR, EGFR, EGfr, EgfR, erbB 1 Proto Oncogene Protein, dbest1, IKK-gamma, TGF-alpha Receptor, 2248, DER flb, erbB-1 Proto-Oncogene Protein, Torpedo/Egfr, c-Crk, dAKT/dPKB, PKB/dAKT, DmelCG4141, F8A5_4, ErbB-1 Receptor, Degfr, experimental procedures, G25K, APDS, NURF-38, CSBP2, MDC1D, DJNK, Transforming-Growth Factor alpha, CSBP1, signaling pathway, enr, DEGFR, PI3KBETA, l(2)05351, Cells, Csbp2, Csbp1, Dmrac1, RAC-ALPHA, Psychological Power, D-p38 MAPK, Grf40 adapter protein, DmelCG4006, D-Egf, Family Receptors, Processes, peltate hair, DRac, Transforming Growth Factor alpha Receptor, mENA, EK2-6, GRB-2-like protein, Exip, LARGE1, dIKK-gamma, c-erbB-1 Protein, c erbB 1 Protein, PRKM15, PIK3, Prkm8, dVps34/PI3K59F, Pi3Kp60, dMPK2, DmIKK-gamma, PRKM14, p38 MAPK, PI3K-dp110, EGFr, Egfr, sapk2a, torpedo/Egfr, dPI3K, TOP, anon-92Ed, D-Rac, EXIP, dNURF, erbB-1, dRac, DmelCG5680, ERK, PRKM1, DJNK/bsk, class I, p38beta, PRKM2, Hrp36, anatomical systems, JTV1, p38Ka, VMD2, MDDGB6, mei-1794, p38Kb, JNK21B1|2, top, BMD, AI848995, PRKM8, Pi3Kp110, DmRAC, BC023857, GRB2L, P110BETA, CG12749, PI3K21B, AKT, Akt, Drac, Epidermal Growth Factor Urogastrone, Hepatic, HRP36, species, STK26, MCM, Receptor Tyrosine-protein Kinase erbB-1, p38-2, Hep-G2, myelin basic protein kinase activity, CG2248, RP50, Cpk, Elp-B1RB1, Dp38b, SAPK1c, Dp38a, RING finger protein 19A, EGF Receptor, SAPK2A, Hep G2, JNK3alpha1, AA414921, Epidermal Growth Factor Receptor Family Proteins, akt, ErbB, TGF-alpha receptor activity, class II, ERBB, dEGFR1, type III phosphoinositide 3-kinase activity, Proto-Oncogene Protein, MAP-2 kinase activity, Protein GADS, DAkt1, DAKT1, Dsmurf, Cell, PI(3)K, CG12530, cpk, PI3K-92E/Dp110, dSmurf, DmMKK3, IKKgamma, PDIP38, JNK/SAPK, PIK3C1, PKB, CWS6, JNK1, CWS5, p38MAPKK, Smurf ubiquitin ligase, HepG2 Cells, D-JNK, PKB-ALPHA, JNK1A2, CG4006, DER/top, scales, signalling cascade, p38 beta, Dakt1, Nurf38, DmelCG2248, best, Dmikkgamma, P42MAPK, Dub, CDC42, Crk1, Crk3, DmelCG11621, wa-2, CSPB1, CG16910, Hep G2 Cell Line, Drac1b, Drac1a, SAPK1C, caPI3K, dAkt/PKB, 38 kDa DNA polymerase delta interaction protein, CLOVE, signalling process, like-glycosyltransferase, D-MKK3, DmVps34, CRK1, CG5680, IMD14, Erbb, PI3K_68D, PI3K-92D, Power (Psychology), Epidermal Growth Factor, HER Family, Rac1b, Dmp110, Receptor, Dcdc42, BEST, Hep G2 Cell, DER/faint little ball, scale tissue, Nurf 38, CG5373, ATVPS34, sapk2, Mpk2, Mpk3, Hepatoblastoma G2, Mbp1, Crko, Hepatocyte, p42mapk, PI3K, Dp110, D-p38, BSK, Bsk, Crk-II, p38 alpha, NURF, SUB, DSmurf, DmelCG4634, PHOSPHATIDYLINOSITOL 3-KINASE, p38/NURF-38, DmelCG2699, F8A5.4, Hepatic Cell, AI552599, TGF alpha, ARB, p110alpha, mitogen-activated protein kinase activity, Q14, phosphatidylinositol 3-kinase activity, Q16, d-egf-r, mpk2, RK, KIF20A, IKKg, KEY, Key, signal transduction by protein phosphorylation, Psychological, Adapter protein GRID, DMKK3, Pi3K92D, CG4141, ErbB 1, MEK3/MKK3, catalyst activity, Pi3k, AI849689, PI[[3]]K, PKB|Akt, HSPC322, Proto oncogene c ErbB 1 Protein, MP kinase activity, 38, p55alpha, Dmp38a, AHA1, Hematopoietic cell-associated adapter protein GrpL, Dmp38b, ErbB Receptor, DmelCG12749, MBP kinase II activity, P11, c-Jun, D-EGFR, Pi3K, PI3k, CG5475, MCMTC, NISBD2, DER1, D-smurf, single-organism behavior, D-junk, PI3K68D, MAP kinase 2 activity, CG6264, dakt, Wa5, l(2)09261, Process, gyltl1b-b, P110DELTA, PtdIns-3-kinase activity, HER Family Receptors, signal transduction by conformational transition, ERK1, ERK2, CG8556, A230093K24Rik, Erk2, Psychological Powers, Hrb2, l(3)89Bq, RAC1, CG10079, results, D-P38a, vacuolar protein sorting 34, D-Rac 1, D-Rac 2, GrbX, GRBX, dPIK, 1-phosphatidylinositol 3-kinase activity, D-p38b, Hepatic Cells, D-p38a, JNK21B1/2, signaling cascade, Acceptance Process, PKB/Akt, PKB/AKT, p41mapk, dAkt, dAKT, rac1, wa2, Syn, rac2, DmelCG12530, MDDGA6, MAPK, Kenny, P38, KIAA0609, DAkt, C14orf3, acetylglucosaminyltransferase-like 1A, CG12244, dBest1, l(3)04226, HRB87F/hrp36, DPKB, Epistemology, Dm Rac1, SH3-SH2-SH3 adapter Mona, gyltl1b, GADS, pAkt, AU018915, DmelCG4943, JTV-1, p85alpha, dEgfr, HRB87F, mdc1d, Mona, p38alpha, p38, Prkm15, HepG2, Cdc42Dm, PI3K 68_D, LARGE_HUMAN, Prkm14, Proto-oncogene c-Crk, Cell Line, Receptor Tyrosine protein Kinase erbB 1, DRac1, p110D, Dakt, DRac2, DmelCG16910, D-Cdc42, RacB, HEPG2, RacA, p41, dPKB, p40, l(2)57DEFa, dEGFR, HER, DmelCG12304, DRacA, DmHD-33, DRacB, D-CDC42, p120-PI3K, c-ErbB-1 Protein, Powers, 186F5S, BSK/DJNK, droPIK57, AT1G11140, DRAC-PK85, DracA, Xcdc42, l(1)G0252, experimental, Professional Power, CG7393, C-erb, Transforming Growth Factor alpha, dSmurf1, PI3K92E, Drac2, mor1, Drac1, Pi3K_59F, anon-WO0118547.380, type I phosphatidylinositol kinase activity, froggy, CG12298, Gyltl1a, phosphatidylinositol 3-kinase, CrkIII, Dpkb, p38Hog, dp38a, dp38b, Gads, p60, HEP-G2, c-erbB, EGF receptor activity, N38, PHOSPATIDYLINOSITOL 3-KINASE, Egf-r, dmIKKgamma, p42-MAPK, IKK[[gamma]], CDC42Hs, Dp110/PI3K, PI3K-68D/E, reactivity, Mkk3, MKK3, EGF-R, AI747189, methods, DmelCG12244, experimental section, Grf-40, Torpedo/DER, LARGE, c-Jun N-terminal kinase activity, PI3'K, Crk-III, p42 mitogen-activated protein kinase activity, ATP:protein phosphotransferase (MAPKK-activated) activity, top/flb, Family Receptor, BPFD#36, Epidermal Growth Factor-Urogastrone, signalling pathway, PI3K-68D, d-smurf, GRID, IKK, l(2)57EFa, DRAC-PK, signal transduction by cis-phosphorylation, l(2)57Ea, SRF9, Behaviors, Proto-oncogene, cdc42, dP110, JNK, Jnk, Epidermal Growth Factor Receptor Protein Tyrosine Kinase, 6330412C24Rik, DMPK2, p120, Hepatoblastoma G2 Cell Line, anon-sts23, p110, P11/Hrb87F, Vps34p, Dm Cdc42, Crk-I, DMKK3/lic, DmelCG7393, signal transduction by trans-phosphorylation., STRUBBELIG-RECEPTOR FAMILY 9, p38delta, jnk, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, epidermal growth factor receptor activity, DmelCG10079, vps34, group 2, Epidermal Growth Factor Receptor Protein-Tyrosine Kinase, MBP kinase I activity, dp110, D-Akt, Proto-oncogene c-ErbB-1 Protein, Professional, HER Family Receptor, PI3CG, l(2)k16102, PI-3-K, Acceptance, Dbest, PI3K-59F, scale, top/DER, akt1, PI3K-Dp110, dAkt1, mitogen activated kinase activity, DRAC-PK66, Mxi2, POLD4, class III, DCdc42, Sapk2A, ERBB1, HEP G2, MAPK2, p110gamma, Dmcdc42, dp38, Dorfin, Personal Power, EGF, Egf, dakt1, DCDC42, EFG-R, mxi2, Errp, ERT1, PKBalpha, Der, DER, dAKT1, BG:DS00797.3, transforming growth factor-alpha receptor activity, RAC, Rac, response, T19D16.8, DER/torpedo, SCM, HER1, glycosyltransferase-like protein LARGE1, MAP kinase 1 activityDER/faint little ball, Elp-B1RB1, Elp, D-Egf, Logics, Wa5, l(2)09261, determination, 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, c-erbB, EGFr, Egfr, torpedo/Egfr, EGF receptor activity, TOP, Egf-r, DER/top, d-egf-r, egfr, EGF-R, HD-33, El, top/DER, DER/EGFR, EGFR, EGfr, EgfR, dEgfr, chemical analysis., DER flb, top, Torpedo/DER, ERBB1, wa-2, Torpedo/Egfr, EGFR family signaling pathway, flb, top/flb, Degfr, Egf, EFG-R, Errp, l(2)57EFa, Erbb, DEGFR, l(2)57DEFa, l(2)05351, Der, DER, 9030024J15Rik, D-EGFR, dEGFR, l(2)57Ea, transforming growth factor-alpha receptor activity, assay, DmHD-33, DER/torpedo, HER1, NISBD2, DER1DER/faint little ball, Elp-B1RB1, Elp, D-Egf, Wa5, l(2)09261, TGF-alpha receptor activity, EGFR family signaling pathway., 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, c-erbB, EGFr, Egfr, torpedo/Egfr, EGF receptor activity, TOP, Egf-r, DER/top, d-egf-r, egfr, EGF-R, HD-33, El, top/DER, DER/EGFR, EGFR, EGfr, EgfR, dEgfr, DER flb, top, Torpedo/DER, ERBB1, wa-2, Torpedo/Egfr, flb, top/flb, Degfr, Egf, EFG-R, Errp, l(2)57EFa, Erbb, DEGFR, 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, DER1Rac GTPase, Urogastrone Receptor, dmBest1, PRKBA, extracellular signal-regulated kinase activity, GrpL, Akt/PKB, GRPL, pp44mapk, Growth factor receptor-binding protein, SAPKa, dP60, CRKII, Vps34, acetylglucosaminyltransferase-like protein, D-Rac1, HepG2 cell, D-Rac2, DAKT1/PKB, NURF38, DmCDC42, Elp-B1, der, Receptors, Elp-1, Errb1, rac, BcDNA:LD15217, AKT1, p38-alpha, VPS34, 11621, DmelCG6264, Epidermal Growth Factor Receptor Family Protein, p38MAPK, p38a, PIG61, p38ALPHA, Hog, PI-3 kinase, p110-alpha, ErbB-1, Personal, DmelCG8556, LeMPK3, Rac-2, Rac-1, DmelCG12298, Method, epidermal growth factor-activated receptor activity, hnRNP A2/B1, p44mpk, responsivity, Dp38, SCRAMBLED, SAPK1, myd, SAPK2, Mpk34C, JNK-46, p38B, p38A, Dp60, mapk14a, like-acetylglucosaminyltransferase, pp42, DBSK/JNK, Junk, PI3K_59F, hrp40, plant peltate hair, Mbp-1, hnRNP36, PI3-kinase activity, Epidermal Growth Factor Receptor, EGFR family signaling pathway, Hrb87Fa, Dm p38b, Epidermal Growth Factor Receptor Kinase, PI3Kgamma, flb, HepG2 Cell, RacPK, Hrb85CD, Social, MCAP, hrp36, Grf40, TGF-alpha, Smurf, dMKK3, PI3K 68D, 9030024J15Rik, Social Power, GRBLG, CG4943, ESTS:186F5S, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, single organism signaling, Power, DmMPK2, dVps34, dRac1, Elp, EGF Receptors, DEgfr, 6.3.2.-, dJNK, rea, csbp, STRUBBELIG, ERK-2, CG4634, p50alpha, PMK-2, Lack, Procedure, PMK-1, CG2699, DmelCG5373, signal transduction by trans-phosphorylation, Acceptance Processes, Hrb87f, PMK-3, CSBP, torpedo/egfr, DmIKKgamma, AKT/PKB, GTPase Rac1, C530050K14, Double ring-finger protein, dIKK, mKIAA0609, type-1 PI3K, p-Akt, D-MPK2, GRAP-2, TU15B, Urogastrone, activation, egfr, fg, DmelCG5475, CG11621, D-cdc42, Mek3, MEK3, DMEK3, HD-33, El, DmRAC2, DmRAC1, DER/EGFR, EGFR, EGfr, EgfR, erbB 1 Proto Oncogene Protein, dbest1, IKK-gamma, TGF-alpha Receptor, 2248, DER flb, erbB-1 Proto-Oncogene Protein, Methodological, Torpedo/Egfr, c-Crk, dAKT/dPKB, PKB/dAKT, DmelCG4141, F8A5_4, ErbB-1 Receptor, Degfr, G25K, APDS, NURF-38, CSBP2, MDC1D, DJNK, Transforming-Growth Factor alpha, CSBP1, signaling pathway, enr, DEGFR, PI3KBETA, l(2)05351, Cells, Csbp2, Csbp1, Dmrac1, RAC-ALPHA, Psychological Power, D-p38 MAPK, Grf40 adapter protein, DmelCG4006, D-Egf, Family Receptors, Processes, peltate hair, DRac, Transforming Growth Factor alpha Receptor, mENA, EK2-6, GRB-2-like protein, Exip, LARGE1, dIKK-gamma, c-erbB-1 Protein, c erbB 1 Protein, PRKM15, PIK3, Prkm8, dVps34/PI3K59F, Pi3Kp60, dMPK2, DmIKK-gamma, PRKM14, p38 MAPK, PI3K-dp110, EGFr, Egfr, sapk2a, torpedo/Egfr, dPI3K, TOP, anon-92Ed, D-Rac, EXIP, dNURF, Technique, erbB-1, dRac, DmelCG5680, ERK, PRKM1, DJNK/bsk, class I, p38beta, PRKM2, Hrp36, anatomical systems, JTV1, p38Ka, VMD2, MDDGB6, mei-1794, p38Kb, JNK21B1|2, top, BMD, AI848995, PRKM8, Pi3Kp110, DmRAC, BC023857, GRB2L, P110BETA, Study, CG12749, PI3K21B, AKT, Akt, Drac, Epidermal Growth Factor Urogastrone, Hepatic, HRP36, species, STK26, MCM, Receptor Tyrosine-protein Kinase erbB-1, p38-2, Hep-G2, myelin basic protein kinase activity, CG2248, RP50, Cpk, Elp-B1RB1, Dp38b, SAPK1c, Dp38a, RING finger protein 19A, EGF Receptor, SAPK2A, Hep G2, JNK3alpha1, AA414921, Epidermal Growth Factor Receptor Family Proteins, akt, ErbB, TGF-alpha receptor activity, class II, ERBB, dEGFR1, type III phosphoinositide 3-kinase activity, Proto-Oncogene Protein, MAP-2 kinase activity, Protein GADS, DAkt1, DAKT1, Dsmurf, Cell, PI(3)K, CG12530, cpk, PI3K-92E/Dp110, dSmurf, DmMKK3, IKKgamma, PDIP38, JNK/SAPK, PIK3C1, PKB, CWS6, JNK1, CWS5, p38MAPKK, Smurf ubiquitin ligase, HepG2 Cells, D-JNK, PKB-ALPHA, JNK1A2, CG4006, background, DER/top, scales, signalling cascade, p38 beta, Dakt1, Nurf38, DmelCG2248, best, Dmikkgamma, P42MAPK, Dub, CDC42, Crk1, Crk3, DmelCG11621, wa-2, CSPB1, CG16910, Hep G2 Cell Line, Drac1b, Drac1a, plan specification, SAPK1C, caPI3K, dAkt/PKB, 38 kDa DNA polymerase delta interaction protein, CLOVE, signalling process, like-glycosyltransferase, D-MKK3, DmVps34, CRK1, CG5680, IMD14, Erbb, PI3K_68D, PI3K-92D, Power (Psychology), Epidermal Growth Factor, HER Family, Rac1b, Dmp110, Receptor, Dcdc42, BEST, Hep G2 Cell, DER/faint little ball, scale tissue, Nurf 38, CG5373, ATVPS34, sapk2, Mpk2, Mpk3, Hepatoblastoma G2, Mbp1, Crko, Hepatocyte, p42mapk, PI3K, Dp110, D-p38, BSK, Bsk, Crk-II, p38 alpha, NURF, SUB, Techniques, DSmurf, DmelCG4634, PHOSPHATIDYLINOSITOL 3-KINASE, p38/NURF-38, DmelCG2699, F8A5.4, Hepatic Cell, AI552599, TGF alpha, ARB, p110alpha, mitogen-activated protein kinase activity, Q14, phosphatidylinositol 3-kinase activity, Q16, d-egf-r, mpk2, RK, KIF20A, IKKg, KEY, Key, signal transduction by protein phosphorylation, Psychological, Adapter protein GRID, DMKK3, Pi3K92D, CG4141, ErbB 1, MEK3/MKK3, catalyst activity, Pi3k, AI849689, PI[[3]]K, PKB|Akt, HSPC322, Proto oncogene c ErbB 1 Protein, MP kinase activity, 38, p55alpha, Methodological Studies, Dmp38a, AHA1, Hematopoietic cell-associated adapter protein GrpL, Dmp38b, ErbB Receptor, DmelCG12749, MBP kinase II activity, P11, c-Jun, D-EGFR, Pi3K, PI3k, CG5475, MCMTC, NISBD2, DER1, D-smurf, single-organism behavior, D-junk, PI3K68D, MAP kinase 2 activity, CG6264, dakt, Wa5, l(2)09261, Process, gyltl1b-b, P110DELTA, PtdIns-3-kinase activity, HER Family Receptors, signal transduction by conformational transition, ERK1, ERK2, CG8556, A230093K24Rik, Erk2, Psychological Powers, Hrb2, l(3)89Bq, RAC1, CG10079, results, D-P38a, vacuolar protein sorting 34, D-Rac 1, D-Rac 2, GrbX, GRBX, dPIK, 1-phosphatidylinositol 3-kinase activity, D-p38b, Hepatic Cells, D-p38a, JNK21B1/2, signaling cascade, Acceptance Process, PKB/Akt, PKB/AKT, p41mapk, dAkt, dAKT, rac1, wa2, Syn, rac2, DmelCG12530, MDDGA6, MAPK, Kenny, P38, KIAA0609, DAkt, C14orf3, acetylglucosaminyltransferase-like 1A, CG12244, dBest1, l(3)04226, HRB87F/hrp36, DPKB, Epistemology, Dm Rac1, SH3-SH2-SH3 adapter Mona, gyltl1b, GADS, pAkt, AU018915, DmelCG4943, JTV-1, p85alpha, dEgfr, HRB87F, mdc1d, Mona, p38alpha, p38, Prkm15, HepG2, Cdc42Dm, PI3K 68_D, LARGE_HUMAN, Methodological Study, Prkm14, Proto-oncogene c-Crk, Cell Line, Receptor Tyrosine protein Kinase erbB 1, DRac1, p110D, Dakt, DRac2, DmelCG16910, D-Cdc42, RacB, HEPG2, RacA, p41, dPKB, p40, l(2)57DEFa, dEGFR, HER, DmelCG12304, DRacA, DmHD-33, DRacB, D-CDC42, p120-PI3K, c-ErbB-1 Protein, Powers, 186F5S, BSK/DJNK, droPIK57, AT1G11140, DRAC-PK85, DracA, Xcdc42, l(1)G0252, Procedures, Professional Power, CG7393, C-erb, Transforming Growth Factor alpha, dSmurf1, PI3K92E, Drac2, mor1, Drac1, Pi3K_59F, anon-WO0118547.380, type I phosphatidylinositol kinase activity, froggy, CG12298, Gyltl1a, phosphatidylinositol 3-kinase, CrkIII, Dpkb, p38Hog, method, dp38a, dp38b, Gads, p60, HEP-G2, method used in an experiment, c-erbB, Studies, EGF receptor activity, N38, PHOSPATIDYLINOSITOL 3-KINASE, Egf-r, dmIKKgamma, p42-MAPK, IKK[[gamma]], CDC42Hs, Dp110/PI3K, PI3K-68D/E, reactivity, Mkk3, MKK3, EGF-R, AI747189, DmelCG12244, Grf-40, Torpedo/DER, LARGE, c-Jun N-terminal kinase activity, PI3'K, Crk-III, p42 mitogen-activated protein kinase activity, ATP:protein phosphotransferase (MAPKK-activated) activity, top/flb, Family Receptor, BPFD#36, Epidermal Growth Factor-Urogastrone, signalling pathway, PI3K-68D, d-smurf, GRID, IKK, l(2)57EFa, DRAC-PK, signal transduction by cis-phosphorylation, l(2)57Ea, SRF9, Behaviors, Proto-oncogene, cdc42, dP110, JNK, Jnk, Epidermal Growth Factor Receptor Protein Tyrosine Kinase, 6330412C24Rik, DMPK2, p120, Hepatoblastoma G2 Cell Line, anon-sts23, p110, P11/Hrb87F, Vps34p, Dm Cdc42, Crk-I, DMKK3/lic, DmelCG7393, signal transduction by trans-phosphorylation., STRUBBELIG-RECEPTOR FAMILY 9, p38delta, jnk, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, epidermal growth factor receptor activity, DmelCG10079, vps34, group 2, Epidermal Growth Factor Receptor Protein-Tyrosine Kinase, MBP kinase I activity, dp110, D-Akt, Proto-oncogene c-ErbB-1 Protein, Professional, HER Family Receptor, PI3CG, l(2)k16102, PI-3-K, Acceptance, Dbest, PI3K-59F, scale, top/DER, akt1, PI3K-Dp110, dAkt1, mitogen activated kinase activity, DRAC-PK66, Mxi2, POLD4, class III, DCdc42, Sapk2A, ERBB1, HEP G2, MAPK2, p110gamma, introduction, Dmcdc42, dp38, Dorfin, Personal Power, EGF, Egf, dakt1, DCDC42, EFG-R, mxi2, Errp, ERT1, PKBalpha, Der, DER, dAKT1, BG:DS00797.3, transforming growth factor-alpha receptor activity, RAC, Rac, response, T19D16.8, DER/torpedo, SCM, HER1, glycosyltransferase-like protein LARGE1, MAP kinase 1 activityfalseEGFR & ErbB SignalingThe epidermal growth factor receptor (EGFR) signaling pathway is probably the best-studied receptor system in mammalian cells, and it also has become a popular example for employing mathematical modeling to cellular signaling networks. Dynamic models have the highest explanatory and predictive potential; however, the lack of kinetic information restricts current models of EGFR signaling to smaller sub-networks. This work aims to provide a large-scale qualitative model that comprises the main and also the side routes of EGFR/ErbB signaling and that still enables one to derive important functional properties and predictions. Using a recently introduced logical modeling framework, we first examined general topological properties and the qualitative stimulus-response behavior of the network. With species equivalence classes, we introduce a new technique for logical networks that reveals sets of nodes strongly coupled in their behavior. We also analyzed a model variant which explicitly accounts for uncertainties regarding the logical combination of signals in the model. The predictive power of this model is still high, indicating highly redundant sub-structures in the network. Finally, one key advance of this work is the introduction of new techniques for assessing high-throughput data with logical models (and their underlying interaction graph). By employing these techniques for phospho-proteomic data from primary hepatocytes and the HepG2 cell line, we demonstrate that our approach enables one to uncover inconsistencies between experimental results and our current qualitative knowledge and to generate new hypotheses and conclusions. Our results strongly suggest that the Rac/Cdc42 induced p38 and JNK cascades are independent of PI3K in both primary hepatocytes and HepG2. Furthermore, we detected that the activation of JNK in response to neuregulin follows a PI3K-dependent signaling pathway.2013-12-192018-04-152018-04-15230919662154