BioModels

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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. National Centre for Cell Science, Ganeshkhind, Pune-7, India. uddipans@gmail.comuddipans@gmail.comNational Centre for Cell ScienceBIOMD0000000430We mathematically modeled the receptor-dependent mitogen-activated protein kinase (MAPK) signaling by incorporating the regulation through cellular phosphatases. Activation induced the alignment of a phosphatase cascade in parallel with the MAPK pathway. A novel regulatory motif was, thus, generated, providing for the combinatorial control of each MAPK intermediate. This ensured a non-linear mode of signal transmission with the output being shaped by the balance between the strength of input signal and the activity gradient along the phosphatase axis. Shifts in this balance yielded modulations in topology of the motif, thereby expanding the repertoire of output responses. Thus, we identify an added dimension to signal processing wherein the output response to an external stimulus is additionally filtered through indicators that define the phenotypic status of the cell.<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.Different designs of kinase-phosphatase interactions and phosphatase sequestration shapes the robustness and signal flow in the MAPK cascade.Integration of a phosphatase cascade with the mitogen-activated protein kinase pathway provides for a novel signal processing function.Sarma Uddipan U, Ghosh Indira IChaudhri Virendra K VK, Kumar Dhiraj D, Misra Manjari M, Dua Raina R, Rao Kanury V S KVextent, PP2A[[C]], DmErk, extracellular signal-regulated kinase activity, PR53, B Cells, pp44mapk, PR55, Public Sectors, l(3)S026326, Tyro5, Phosphatase, B cell, PP2A[B], A4, pr53, anon-WO0118547.420, raf, phosphorylation, Long Term, Prp4 protein kinase activity, DmelCG7109, MKP3, B', LeMPK3, l(3)S031807, ATP-protein transphosphorylase activity, PP2A 28D, Method, p44mpk, responsivity, ATP:protein phosphotransferase (non-specific) activity, Dp38, PP2A[C], Kinase, Public Enterprise, SAPK2, l(3)01436, SEM, Sem, WMS, l(3)S110815, MAP-k, gamma sarcoglycan, Pp2A, pp42, PP2a, Draf-1, l(3)S026226, l(3)S027313, EK5, Nonmigrant, l(3)S141309, MAP kinase kinase 4 activity, aar, Dsor2, cell sheath, sem, Phosphomonoesterases, pp2a, D-raf1, Transient, l(3)02414, DmelCG6235, PR65, l(3)S035505b, PP2A, l(3)S048006, Homo sapiens disease, Pp2A-28D, l(3)S048013, CG14080, CG14081, ATP Phosphotransferases, phosphatase, PP2A[A], SGS, ERK-A, p82 kinase activity, l(3)S067915, anatomical protrusion, dpERK, dpErk, l(1)phl, B Lymphocytes, 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, 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, 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, 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, dPP2A-Balpha, ligand, proliferating, MAPK signaling, STK32, PCBC, 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, 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, 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, mpk1, Effect, human disease, Erk/Map kinase, l(3)s1801, Migrant Worker, pre-mortem, l(3)S049902, 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, 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, BcDNA:RE08694, protein glutamyl kinase activity, l(2R)EMS45-39, Draf1, raf1, CAPB, PTPA, DmelCG12559, MAP kinase kinase 7 activity, p38, CG6235, l(3)S061915, MASS, gamma (35kDa dystrophin-associated glycoprotein), 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, rafl, Proliferating, other disease, ribosomal S6 protein kinase activity, calcium/phospholipid-dependent protein kinase activity, SGCG_HUMAN, HH19, Procedures, GroupII, experimental, MAPKK1, 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, Public., assay, response, RAF, Raf, MKP-3, B-lymphocyte, MAP kinase 1 activity, A-kinase activity, CG2845MAPK signaling., MAPKKK cascade during sporulation, ERK/MAPK cascade, MAPK signallingglycogen synthase kinase activity, c-Raf, DmErk, extracellular signal-regulated kinase activity, pp44mapk, protein kinase A activity, Activity, Tyro5, Phosphatase, Mpk2, p42mapk, raf, Social Controls, prevention, Prp4 protein kinase activity, SR2-1, dmTAF[[II]]230, Phosphatases, Hydrolase, Mitogen Activated Protein Kinase, LeMPK3, Mitogen-Activated Protein, ATP-protein transphosphorylase activity, p44mpk, kinase-related transforming protein, ATP:protein phosphotransferase (non-specific) activity, Dp38, mitogen-activated protein kinase activity, Protein Kinases, Kinase, SAPK2, mpk1, SEM, Sem, prevention and control, Formal Social Controls, MAP-k, Erk/Map kinase, reference sample, TFIID TAF250, Draf-1, pp42, cel, EK5, C2, DERK-A, Dsor2, Craf1, E(sina)7, sem, Rl, D-raf1, Phosphomonoesterases, Raf kinase activity, Social, preventive measures, serine kinase activity, MP kinase activity, DERK, atypical protein kinase C activity, MBP kinase II activity, mitogen-activated S6 kinase activity, protein-aspartyl kinase activity, dERK, phosphatase, single organism signaling, p82 kinase activity, ERK-A, Mitogen-Activated, 6430402F14Rik, MAP kinase 2 activity, dTAF[[II]]230, preventive therapy, dpERK, dpErk, l(1)phl, Mapk, betaIIPKC, Erk1, TAF200, ERK1, ERK2, mapk1a, DmMAPK, PMK-2, dp-ERK, PMK-1, TAFII-250, cRaf, TAF250/230, PMK-3, M phase-specific cdc2 kinase activity, Wee-kinase activity, TAFII250, mapk1b, MapK, MAPK, pMAPK, pMapK, v-Raf, serine protein kinase activity, DRaf1, erk2, mapk, activation, l(1)G0475, phosphorylase B kinase kinase activity, ERKa, DmERKA, l(1)pole hole, rl/MAPK, BcDNA:RE08694, protein glutamyl kinase activity, CRAF, l(2R)EMS45-39, Draf1, raf1, CAPB, DmelCG12559, Control, non-specific serine/threonine protein kinase activity, p38, l(2)41Ac, l(1)polehole, Controls, D-raf, CG17603, TAF[[II]], DpErk, DpERK, ErkA, ERKA, hydroxyalkyl-protein kinase activity, WEE1Hu, CT34260, Phosphohydrolase, CMD1NN, dpERk, Taf250, MITOGEN-ACTIVATED PROTEIN KINASE, serine-specific protein kinase activity, SR3-5, epsilon PKC, Phosphoric, HIPK2, SAPK, cytidine 3', C110, EG:BACH48C10.3, BB129353, mitogen-activated protein kinase 1, Wee 1-like kinase activity, Hydrolases, Protein Kinase, Regulation, pERK, TAF230, rafl, Regulations, F14N23_9, ribosomal S6 protein kinase activity, calcium/phospholipid-dependent protein kinase activity, d230, glycogen synthase A kinase activity, GroupII, glycogen synthase kinase 3 activity, NS5, 12559, F14N23.9, DRaf, stalk, dTAFII250, Monoester Hydrolase, EfW1, draf, phosphorylase b kinase kinase activity, EK2-1, Proto-oncogene c-RAF, Hek5, dmTAF1, Taf230, serine(threonine) protein kinase activity, ribosomal protein S6 kinase II activity, Raf1, D-RAF, D-Raf, T-antigen kinase activity, Erk, ERK, TAF250, PRKM1, galactosyltransferase-associated kinase activity, protein-serine kinase activity, PRKM2, Taf200, Mitogen-Activated Protein Kinase, dTAF[[II]]250, DmelCG2845, cell, xp42, STK32, PCBC, Phl, Taf1p, Mitogen Activated Protein Kinases, p42 mitogen-activated protein kinase activity, CG18732, culm, ATP:protein phosphotransferase (MAPKK-activated) activity, erk, Phosphoric Monoester Hydrolase, dTAF250, protein kinase (phosphorylating) activity, protein-cysteine kinase activity, Raf-1, l(1)raf, Hpr kinase activity, ATMPK1, Draf, rll, DmERK-A, STK26, p38-2, TAF, casein kinase (phosphorylating) activity, myelin basic protein kinase activity, Controlled, Controlling, ert1, TAF[[II]]250, DRT, Formal Social Control, axis, raf-1, prkm2, stress-activated kinase activity, prkm1, CT39192, MAP-2 kinase activity, l(3)84Ab, l(1)2Fe, BG:DS00004.13, protein serine kinase activity, motif, Cell, protein phosphokinase activity, dTAF230, p38delta, Phosphomonoesterase, twitchin kinase activity, Raf/phl, 2.7.11.1, PKA, PKC, Social Control, p230, stress-activated protein kinase activity, AP50 kinase activity, mapk2, mapk1, MBP kinase I activity, TAF[[II]]250/230, TFIID, AA990557, protein kinase p58 activity, Xp42, serine/threonine protein kinase activity, threonine-specific protein kinase activity, Taf[[II]]250, Phosphoric Monoester, CG12559, TAF[[II]]230, Kinases, mitogen activated kinase activity, prophylaxis, Su(Raf)2B, dpERK1, phosphoric monoester hydrolase activity, EY2-2, TAF[II]250, l(1)ph, dsk1, 5'-cyclic monophosphate-responsive protein kinase activity, atypical PKC activity, 11-29, Phosphohydrolases, l(1)polehole/draf, D-ERK, DmelCG17603, D830050J10Rik, signalling process, TAF1., dpMAPK, control, EPHT3, regulation, RAF, Raf, ph, protein serine-threonine kinase activity, General activity, SAP kinase activity, A-kinase activity, MAP kinase 1 activity, CG2845Transphosphorylases, Phosphoric Monoester, MAPK signaling., Kinases, Phosphatase, ERK/MAPK cascade, phosphoric monoester hydrolase activity, Transphosphorylase, Monoester Hydrolase, Phosphomonoesterases, Phosphotransferases, Phosphoric Monoester Hydrolase, Phosphohydrolases, Phosphatases, Phosphomonoesterase, Hydrolase, Phosphohydrolase, MAPKKK cascade during sporulation, MAPK signalling, Phosphoric, Kinase, ATP Phosphotransferases, Hydrolases, phosphatase, Phosphotransferase, ATPfalseSarma2012 - Interaction topologies of MAPK cascade (M4_K2_USEQ) Sarma2012 - Interaction topologies of MAPK cascade (M4_K2_USEQ) 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 . Models that correspond to type M4 with mass-action kinetics K2, in four condition 1) USEQ [ MODEL1204280020 - M4_K2_USEQ], 2) PSEQ [ MODEL1204280024 - M4_K2_PSEQ], 3) QSS_USEQ [ MODEL1204280036 - M4_K2_QSS_USEQ] and 4) QSS_PSEQ [ MODEL1204280040 - M4_K2_QSS_PSEQ] are available from the curated branch. The remaining 36 models can be accessed from the non-curated branch. This model [ MODEL1204280020 - M4_K2_USEQ] correspond to type M4 with mass-action kinetics K2, in USEQ (Unsequestrated ) condition. This model is described in the article: Different designs of kinase-phosphatase interactions and phosphatase sequestration shapes the robustness and signal flow in the MAPK cascade. Sarma U, Ghosh I. BMC Syst Biol. 2012 Jul 2;6(1):82. Abstract: BACKGROUND: 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. RESULTS: We 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. CONCLUSIONS: 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. This model is hosted on BioModels Database and identified by: MODEL1204280020 . 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. 2024-08-212024-09-022012-04-28BIOMD00000004302274829519897477MODEL1204280020BIOMD0000000430GO:0006461GO:0016310GO:0000165GO:0005623GO:0043241GO:0016311C00562131567P27361Q02750P04049P51452P61225