BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000030?filename=BIOMD0000000030.pdfhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000030?filename=BIOMD0000000030-biopax2.owlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000030?filename=BIOMD0000000030-biopax3.owlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000030?filename=BIOMD0000000030_url.xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000030?filename=BIOMD0000000030_urn.xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000030?filename=BIOMD0000000030.scihttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000030?filename=BIOMD0000000030.pnghttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000030?filename=BIOMD0000000030.xpphttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000030?filename=BIOMD0000000030.vcmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000030?filename=BIOMD0000000030.mprimaryOK200Nicolas Le NovèreManually curatedL2V1https://www.ebi.ac.uk/biomodels/BIOMD000000003014744999falseBioModelsSBMLModelsMarkevich2004 MAPK AllRandomElementary2004MODEL6618676537Markevich NI, Hoek JB, Kholodenko BNMarkevich NI14744999,
Mitogen-activated protein kinase (MAPK) cascades can operate as bistable switches residing in either of two different stable states. MAPK cascades are often embedded in positive feedback loops, which are considered to be a prerequisite for bistable behavior. Here we demonstrate that in the absence of any imposed feedback regulation, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site MAPK phosphorylation and dephosphorylation. Importantly, the reported kinetic properties of the kinase (MEK) and phosphatase (MKP3) of extracellular signal-regulated kinase (ERK) fulfill the essential requirements for generating a bistable switch at a single MAPK cascade level. Likewise, a cycle where multisite phosphorylations are performed by different kinases, but dephosphorylation reactions are catalyzed by the same phosphatase, can also exhibit bistability and hysteresis. Hence, bistability induced by multisite covalent modification may be a widespread mechanism of the control of protein activity.. null, 164.
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107, USA.lenov@ebi.ac.ukEBML-EBIBIOMD0000000030Mitogen-activated protein kinase (MAPK) cascades can operate as bistable switches residing in either of two different stable states. MAPK cascades are often embedded in positive feedback loops, which are considered to be a prerequisite for bistable behavior. Here we demonstrate that in the absence of any imposed feedback regulation, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site MAPK phosphorylation and dephosphorylation. Importantly, the reported kinetic properties of the kinase (MEK) and phosphatase (MKP3) of extracellular signal-regulated kinase (ERK) fulfill the essential requirements for generating a bistable switch at a single MAPK cascade level. Likewise, a cycle where multisite phosphorylations are performed by different kinases, but dephosphorylation reactions are catalyzed by the same phosphatase, can also exhibit bistability and hysteresis. Hence, bistability induced by multisite covalent modification may be a widespread mechanism of the control of protein activity.Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades.Markevich Nick I NI, Hoek Jan B JB, Kholodenko Boris N BNextracellular signal-regulated kinase activity, GrpL, DmErk, pp44mapk, GRPL, DSORT, CRKII, Tyro5, fond, MEK1/2, CycEI, p38-alpha, phosphorylation, p38MAPK, p38a, Prp4 protein kinase activity, Hog, p38ALPHA, protein polypeptide chains, MKP3, LeMPK3, ATP-protein transphosphorylase activity, p44mpk, hnRNP A2/B1, ATP:protein phosphotransferase (non-specific) activity, Dp38, Kinase, SAPK2, Mpk34C, SEM, Sem, p38B, p38A, MAP-k, mapk14a, pp42, hrp40, EK5, hnRNP36, Dsor2, proteins, Dm p38b, Hrb87Fa, sem, DSor1, DSOR1, Hrb85CD, hrp36, Grf40, dMKK3, CG14080, CG14081, ATP Phosphotransferases, phosphatase, GRBLG, ESTS:186F5S, DmMPK2, p82 kinase activity, ERK-A, dpERK, dpErk, 6.3.2.-, csbp, ERK-1, ERK-2, betaIIPKC, DmMAPK, dephosphorylation, PMK-2, PMK-1, dp-ERK, Cyc E, Acceptance Processes, PMK-3, Hrb87f, CSBP, Wee-kinase activity, BG:DS07108.3, Double ring-finger protein, pMAPK, pMapK, D-MPK2, DMEK-1, GRAP-2, l(2)05206, EK1-1, DmelCG5475, Mek3, MEK3, DMEK3, DmERKA, rl/MAPK, non-specific serine/threonine protein kinase activity, l(2)41Ac, c-Crk, Mtap2k, C78273, CSBP2, CSBP1, CT34260, dpERk, MITOGEN-ACTIVATED PROTEIN KINASE, serine-specific protein kinase activity, HIPK2, SAPK, cytidine 3', Csbp2, Csbp1, Feedbacks, mitogen-activated protein kinase 1, Wee 1-like kinase activity, 9030612K14Rik, p44erk1, D-p38 MAPK, DmelCG14080, cycline, glycogen synthase A kinase activity, region or site annotation, Processes, DmcyclinE, glycogen synthase kinase 3 activity, 12559, F14N23.9, protein-containing complex, Exip, phosphorylase b kinase kinase activity, EK2-1, cdi7, PRKM15, pyst1, AA407128, cyclinE, dMPK2, p38 MAPK, PRKM14, sapk2a, Cdi7, CDI7, Prkm1, Prkm3, ribosomal protein S6 kinase II activity, EXIP, MAP kinase cascade, ERK, Erk, PRKM1, p38beta, PRKM3, PRKM2, protein-serine kinase activity, positional, Hrp36, JTV1, p38Ka, p38Kb, absent from organism, MAPK signaling, STK32, PCBC, General activity., MEK 7, AI848995, DmcycE, BC023857, GRB2L, erk, CG12749, protein-cysteine kinase activity, MAP kinase kinase kinase cascade, Hpr kinase activity, rll, HRP36, STK26, SOR, Sor, p38-2, myelin basic protein kinase activity, Dp38b, Dp38a, RING finger protein 19A, SAPK2A, DRT, Esrk1, mkp-3, stress-activated kinase activity, Phosphorylations, MAP-2 kinase activity, sor, protein serine kinase activity, MK, protein phosphokinase activity, DmMKK3, PKA, l(2)k02514, DmCycE, native protein, PKC, p38MAPKK, stress-activated protein kinase activity, mapk2, mapk1, Mek, MEK, p38 beta, protein kinase p58 activity, DMKP-3, serine/threonine protein kinase activity, 1300019I03Rik, CG12559, l(2)k02602, P42MAPK, dpERK1, mek, Dmkp3, Crk1, Crk3, CSPB1, dsk1, 5'-cyclic monophosphate-responsive protein kinase activity, atypical PKC activity, extracellular, D-CycE, 38 kDa DNA polymerase delta interaction protein, AU018647, D-MKK3, binding_or_interaction_site, dpMAPK, CRK1, regulation, p44mapk, protein serine-threonine kinase activity, SAP kinase activity, glycogen synthase kinase activity, protein kinase A activity, dsor1, Activity, sapk2, ERK/MAPK cascade, Mpk2, Mpk3, Crko, D-MEK/Dsor, p42mapk, protein, D-p38, PRKMK7, Crk-II, p38 alpha, binding site, SR2-1, P44ERK1, Ccne, kinase-related transforming protein, Su(Raf)34B, mitogen-activated protein kinase activity, Q14, Q16, protein aggregate, RK, mpk2, mpk1, Erk/Map kinase, DMKK3, reference sample, MEK3/MKK3, DERK-A, behavioral response to stimulus, E(sina)7, Rl, Raf kinase activity, MP kinase activity, serine kinase activity, DERK, Dmp38a, AHA1, atypical protein kinase C activity, Dmp38b, MAPKKK cascade during sporulation, MBP kinase II activity, DmelCG12749, P11, mitogen-activated S6 kinase activity, ATP - protein phosphotransferase (MAPKK-activated) activity, protein-aspartyl kinase activity, dERK, CG5475, dSor1, ATP, single-organism behavior, MNK1, Mnk1, MAP kinase 2 activity, SAPKK4, Process, sor/MEK1, Mapk, D-sor-1, Erk1, DSor, ERK1, ERK2, mapk1a, Erk2, A230093K24Rik, Hrb2, br37, DRODSOR1, D-P38a, MAPK signal transduction, GrbX, D-p38b, M phase-specific cdc2 kinase activity, D-p38a, Acceptance Process, p41mapk, Syn, MapK, mapk1b, MAPK, P38, C14orf3, serine protein kinase activity, erk2, mapk, region, dSor, CG12244, HRB87F/hrp36, phosphorylase B kinase kinase activity, ERKa, Transphosphorylases, absence, GADS, BcDNA:RE08694, positional polypeptide feature, protein glutamyl kinase activity, JTV-1, l(2R)EMS45-39, CAPB, HRB87F, Mona, DmelCG12559, p38alpha, p38, Prkm15, Prkm14, Proto-oncogene c-Crk, DpErk, DpERK, dMEK, ErkA, ERKA, hydroxyalkyl-protein kinase activity, HUMKER1A, WEE1Hu, l35Dd, p41, epsilon PKC, MAPK signalling, p40, P44MAPK, p44, Dsor, DmelCG12304, 186F5S, pERK, F14N23_9, ribosomal S6 protein kinase activity, calcium/phospholipid-dependent protein kinase activity, MAPKK7, l(1)G0252, HH19, GroupII, CG7393, cycE, l(2)br37, D-mek, CYCLE, CrkIII, p38Hog, dp38a, dp38b, Hek5, HS44KDAP, Gads, polypeptide chain, Dmek, serine(threonine) protein kinase activity, p42-MAPK, JNKK2, Phosphotransferase, CG15793, T-antigen kinase activity, galactosyltransferase-associated kinase activity, Mkk3, MKK3, CYCE, DmelCG12244, DmelCG3938, xp42, MKK7, CyclE, 3938, Transphosphorylase, D-sor, p42 mitogen-activated protein kinase activity, Crk-III, CG18732, ATP:protein phosphotransferase (MAPKK-activated) activity, l(2)k05007, protein kinase (phosphorylating) activity, Erk-1, dm-cycE, GRID, Raf-1, ATMPK1, site, DmERK-A, Behaviors, casein kinase (phosphorylating) activity, D-Mek, D-MEK, behaviour, Controlled, Controlling, ert1, MAPKKK cascade, DMPK2, protein complex, prkm2, anon-sts23, prkm1, CT39192, P11/Hrb87F, mitogen-activated protein kinase cascade, Crk-I, DMKK3/lic, Phosphotransferases, DmelCG7393, p38delta, MEK/Dsor1, twitchin kinase activity, natural protein, group 2, AP50 kinase activity, Protein, MBP kinase I activity, CyeE, D-SOR, D-Sor, Xp42, threonine-specific protein kinase activity, DmelCG15793, Acceptance, MAPKK, Exhibit, mitogen activated kinase activity, Kinases, INSDC_feature:misc_binding, Su(Raf)2B, Mxi2, l(2)35Dd, mkp3, SAPKK-4, Sapk2A, phosphoric monoester hydrolase activity, EY2-2, PYST1, MAPK2, MAPK1, dp38, Dorfin, requirements, D-ERK, mxi2, behavioural response to stimulus, ERT1, Ert2, ERT2, EPHT3, p44-MAPK, p44-ERK1, BG:DS00797.3, MKP-3, CG3938, MAP kinase 1 activity, A-kinase activityAcid, Plxn1, Nukleinsaeure, YB, acide nucleique, DmelCG2706, AUTSX5, number, DXS648, nov, Copyrights, acido nucleico, IGFBP9, CCN3, mKIAA4053, QM, free, presence, fs(1)Y[b], Nucleic, IBP-9, count in organism, acides nucleiques, acidos nucleicos, Yb, L10, IGFBP-9, nucleic acids, C130088N23Rik, Nucleic Acid, Nukleinsaeuren, EG:95B7.8, 2600013D04Rik, NA, NOV, Acids, quantitative, DXS648E, NOVh, PlexA1, Nucleic., CG2706, fs(1)M104, Data Base, presence or absence in organismTransphosphorylases, biological signaling, protein complex, Kinases, ATP., Phosphorylations, proteins, protein, Transphosphorylase, protein-containing complex, phosphorylation, Phosphotransferases, signalling, protein polypeptide chains, signalling process, native protein, natural protein, polypeptide chain, signaling process, Protein, Kinase, protein aggregate, ATP Phosphotransferases, Phosphotransferase, single organism signalingfalseMarkevich2004_MAPK_AllRandomElementary
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2012-05-152005-05-262005-09-13BIOMD00000000302.7.12.23.1.3.16REACT_1780REACT_495REACT_2247REACT_13614744999MODEL6618676537BIOMD0000000030GO:0000165GO:0005623GO:0051019GO:0031434GO:0004708GO:0018108GO:0018107GO:0000187GO:0006470GO:0000188GO:00432418355P26696Q05116Q90W58