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Previous studies have suggested that positive feedback loops and ultrasensitivity are prerequisites for bistability in covalent modification cascades. However, it was recently shown that bistability and hysteresis can also arise solely from multisite phosphorylation. Here we analytically demonstrate that double phosphorylation of a protein (or other covalent modification) generates bistability only if: (a) the two phosphorylation (or the two dephosphorylation) reactions are catalyzed by the same enzyme; (b) the kinetics operate at least partly in the zero-order region; and (c) the ratio of the catalytic constants of the phosphorylation and dephosphorylation steps in the first modification cycle is less than this ratio in the second cycle. We also show that multisite phosphorylation enlarges the region of kinetic parameter values in which bistability appears, but does not generate multistability. In addition, we conclude that a cascade of phosphorylation/dephosphorylation cycles generates multiple steady states in the absence of feedback or feedforward loops. Our results show that bistable behavior in covalent modification cascades relies not only on the structure and regulatory pattern of feedback/feedforward loops, but also on the kinetic characteristics of their component proteins.. null, 273.
Centre for Research in Theoretical Chemistry, Scientific Park of Barcelona, Spain.viji@ebi.ac.ukEMBL-EBIBIOMD0000000258Previous studies have suggested that positive feedback loops and ultrasensitivity are prerequisites for bistability in covalent modification cascades. However, it was recently shown that bistability and hysteresis can also arise solely from multisite phosphorylation. Here we analytically demonstrate that double phosphorylation of a protein (or other covalent modification) generates bistability only if: (a) the two phosphorylation (or the two dephosphorylation) reactions are catalyzed by the same enzyme; (b) the kinetics operate at least partly in the zero-order region; and (c) the ratio of the catalytic constants of the phosphorylation and dephosphorylation steps in the first modification cycle is less than this ratio in the second cycle. We also show that multisite phosphorylation enlarges the region of kinetic parameter values in which bistability appears, but does not generate multistability. In addition, we conclude that a cascade of phosphorylation/dephosphorylation cycles generates multiple steady states in the absence of feedback or feedforward loops. Our results show that bistable behavior in covalent modification cascades relies not only on the structure and regulatory pattern of feedback/feedforward loops, but also on the kinetic characteristics of their component proteins.Bistability from double phosphorylation in signal transduction. Kinetic and structural requirements.Ortega Fernando F, Garcés José L JL, Mas Francesc F, Kholodenko Boris N BN, Cascante Marta Msignal transduction by protein phosphorylation, Signal Transduction Systems, Signal Transductions, Pathway, System, Receptor-Mediated, Phosphorylations, signal transduction by conformational transition, Signal, Receptor-Mediated Signal Transductions, Pathways, Signal Transduction System, Signal Pathways, Signal Transduction Pathway, phosphorylation, signal transduction by trans-phosphorylation, Receptor Mediated Signal Transduction, Signal Transduction, signaling cascade, signalling pathway, signaling pathway, Signal Pathway., Receptor-Mediated Signal Transduction, Systems, signal transduction by cis-phosphorylation, Signal Transduction Pathways, Transductions, signalling cascade, Cell Signaling, TransductionUVO Gene Mutation, Anti-HBsAb Positive, Beta Gene Mutation, Steady, H. pylori Positive, fond, Progesterone Receptor Positive, CycEI, FGFBR Gene Rearrangement, ERBB2 Amplification, phosphorylation, Positive Charge, protein polypeptide chains, Permutation, RET/PTC Rearrangement, Hepatitis C Virus RNA Positive, p53 Mutation, PGR Positive, 0, HCV Antibody Positive, Nuclear Receptor Subfamily 3 Group A Member 1 Positive, No Active Time, Erg-3 Gene Rearrangement, CD332 Gene Mutation, Ha-ras Gene Mutation, Methylated MGMT Promoter, EXPRESSED, HRas Proto-Oncogene, ERA Positive, G Protein Subunit Alpha q Gene Mutation, IDH Gene Mutation, CD324 Gene Mutation, TRT Promoter Mutation, Hepatitis B Virus Core Antibody Positive, c-KIT Positive, Flavoprotein Subunit of Complex II Positive, GAQ Gene Mutation, Met Proto-Oncogene (Hepatocyte Growth Factor Receptor) Gene Amplification, B7H1 Positive, BEK Gene Mutation, proteins, FGFR1 Gene Rearrangement, node-positive, Cadherin 1 Gene Mutation, PD-L1+, ESTRB Positive, XH2 Gene Mutation, Did, NEU Gene Mutation, v-raf Murine Sarcoma Viral Oncogene Homolog B1 Gene Rearrangement, Catenin Beta 1 Gene Mutation, FGFR3 Gene Mutation, ER Beta Positive, SDHB Positive, K-RAS Mutation, CD331 Gene Rearrangement, Hepatitis B DNA Positive, C-HA-RAS1 Gene Mutation, s, Telomerase Reverse Transcriptase Gene Promoter Mutation, MET Amplification, Lesser Than, ZNF-HX Gene Mutation, Parameter, Parameter Value, Methylated MGMT Gene Promoter, ERBB2 Gene Amplification, LOINC Axis 1, Beta Catenin Gene Mutation, Add, Human Immunodeficiency Virus Positive, KGFR Gene Rearrangement, c-erbB2 Gene Amplification, B-RAF Gene Rearrangement, Anti-HBc Positive, Zero Activity Time, dephosphorylation, Hepatitis B Virus Surface Antibody Positive, Cyc E, Estrogen Receptor Alpha Positive, Acceptance Processes, Alpha 11 Gene Mutation, CD331 Gene Mutation, ERB Positive, BG:DS07108.3, SDHIP Positive, Do, Cadherin, JKT4 Gene Rearrangement, Data Change Date, FGFR-2 Gene Rearrangement, FLT2 Gene Mutation, FGFR-1 Gene Rearrangement, l(2)05206, RET Gene Rearrangement, CMC1 Gene Mutation, Adapt, NRAS Gene Mutation, P53 Gene Mutation, ECAD Gene Mutation, Guanine Nucleotide-Binding Protein, PAX8 Gene Rearrangement, NR3A1 Positive, proportionality, rate, Keratinocyte Growth Factor Receptor Gene Rearrangement, HER2 Amplification, EST2 Promoter Mutation, Present, Component, ESR Positive, PDCD1L1 Positive, CD333 Gene Mutation, Positive Epstein-Barr Virus Test, Positive EBV Serum Test, IDH Gene Family Mutation, FGFBR Gene Mutation, N-RAS Gene Mutation, HER2/Neu Amplification, TCS1 Promoter Mutation, Arrangement number, KRAS Gene Mutation, Feedbacks, Expression of PD-L1, Previous, BFGFR Gene Mutation, SDHF Positive, Nuclear Receptor Subfamily 3 Group A Member 2 Positive, cycline, {STEP}, conformation, region or site annotation, Processes, BRCA1-Associated Protein 1 Gene Mutation, CDHE Gene Mutation, DmcyclinE, HCV RNA Positive, Succinate Dehydrogenase [Ubiquinone] Iron-Sulfur Subunit, protein-containing complex, Hepatitis B Virus Surface Antigen Positive, STEPS Intervention, ER+, cdi7, Receptor Tyrosine Kinase Gene Amplification, FGFR1 Gene Mutation, p55 Gene Rearrangement, FLG Gene Rearrangement, cyclinE, Functional Component, PDCD1LG1 Positive, Cdi7, CDI7, Gene Products, G Protein Subunit Alpha 11 Gene Mutation, B7-H Positive, Modification, ETV Rearrangement, androgen receptor positive, Cadherin-Associated Protein, positional, proportion, HBs Positive, MGMT Gene Methylation, Positive Number, Hepatitis B Core Antibody Positive, absent from organism, Former, positive test result, v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog Gene Mutation, GNAQ Gene Mutation, DmcycE, PD-L1 Positive, BEK Gene Rearrangement, RET Rearrangement, CTNNB1 Gene Mutation, FGFR2 Gene Rearrangement, Catalytic, RAD54 Homolog Gene Mutation, ANO1 Positive, RAD54 Gene Mutation, Expression, HER-2 Gene Amplification, CD117 Positive, FGFR2 Gene Mutation, Positive EBV Test, Adapted, Helicobacter pylori Positive, LT, PR Positive, ESRB Positive, Hepatitis B Surface Protein Antigen Positive, Proteins, Phosphorylations, Estrogen Receptor Positive, Zero Active Time, Catalysis, B-RAF1 Gene Rearrangement, Addition, Positive Finding, ATRX, l(2)k02514, native protein, DmCycE, Have, BRAF Gene Rearrangement, GNA11 Gene Mutation, Input Parameter, FLG Gene Mutation, PAX8 Rearrangement, Androgen Receptor Positive, Medical Order, HGFR Gene Amplification, Hepatocyte Growth Factor Receptor Gene Amplification, ESR1 Positive, MET Gene Amplification, c-MET Gene Amplification, ER-Alpha Positive, Modified, Methylated MGMT, l(2)k02602, HBcAb Positive, Regulator, Protein., ERG Rearrangement, Tumor Protein p53 Gene Mutation, HBsAg Positive, IP Positive, Changed, Hepatitis B Surface Antigen Positive, Anti-HCV Antibody Positive, TERT Gene Promoter Mutation, primary structure of sequence macromolecule, {Step}, N-RAS Mutation, FLT-2 Gene Mutation, ETS Transcription Factor ERG Gene Rearrangement, D-CycE, Gene Proteins, Ret Proto-Oncogene Rearrangement, IDH Mutation, CEK Gene Mutation, 1p/19q Co-deletion, quotient, SDHA Positive, Q Polypeptide Gene Mutation, Drug Product Component, Alpha-11 Gene Mutation, Succinate Dehydrogenase [Ubiquinone] Flavoprotein Subunit, Chromatin Remodeler Gene Mutation, Estrogen Receptor 2 Positive, XNP Gene Mutation, O-6-Methylguanine-DNA Methyltransferase Gene Promoter Methylation, Previously, Fibroblast Growth Factor Receptor 1 Gene Mutation, ER Positive, v-Ets Erythroblastosis Virus E26 Oncogene Like Gene Rearrangement, Feature, Hepatitis C Viral RNA Positive, FLT-2 Gene Rearrangement, JKT4 Gene Mutation, protein, AR+, KRAS Mutation, HRAS1 Gene Mutation, G-ALPHA-q Gene Mutation, BAP1 Gene Mutation, ESR-Beta Positive, Fibroblast Growth Factor Receptor 2 Gene Rearrangement, FGFR-3 Gene Rearrangement, Ccne, KGFR Gene Mutation, protein aggregate, v-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 Gene Mutation, TP53, Abnormal, gene expression, estrogen receptor positive, Estrogen Receptor Beta Positive, DOG1 Positive, Alpha Thalassemia/Mental Retardation Syndrome X-Linked Gene Mutation, behavioral response to stimulus, ETV Family Gene Rearrangement, Ets Variant Family Rearrangement, FLT2 Gene Rearrangement, Rearrangement identified, FGFR3 Gene Rearrangement, c-Met Gene Amplification, STEPS to Enhance Physical Activity (STEPS), ECT1 Gene Mutation, Estrogen Receptor 1 Positive, PR+, FMS-Like Tyrosine Kinase 2 Gene Rearrangement, Fibroblast Growth Factor Receptor 2 Gene Mutation, Had, IDH Family Mutation, CD333 Gene Rearrangement, Anti-Hepatitis B Core Antibody Positive, B7 Homolog 1 Positive, Beta 1 (88kD) Gene Mutation, Anti-Hepatitis C Antibody Positive, Less Than, Positive, Has, ATRX Gene Mutation, ratio, single-organism behavior, ERG Gene Rearrangement, Sequence of Planned Assessment Schedule, Anti-HBs Antibody Positive, Programming Parameter, Process, TP53 Gene Mutation, 1p/19q co-deletion, KIT Proto-Oncogene Tyrosine Protein Kinase Positive, v-Ha-ras Harvey Rat Sarcoma Viral Oncogene Homolog Gene Mutation, HER2 Gene Mutation, Positive Estrogen Receptor, br37, results, HBsAb Positive, K-SAM Gene Mutation, Gene Expression, Succinate Dehydrogenase Complex Flavoprotein Subunit A Positive, Acceptance Process, Hepatitis B Surface Antibody Positive, STEPS to Enhance Physical Activity, Population Parameter, HIV Positive, Succinate Dehydrogenase Complex Iron Sulfur Subunit B Positive, Does, KRAS2 Gene Mutation, region, HIV positive, 1p/19q Codeletion, POSITIVE, Guanine Nucleotide Binding Protein (G Protein), Yes, absence, Element, Paired Domain Gene 8 Gene Rearrangement, positional polypeptide feature, SDH2 Positive, Programmed Cell Death 1 Ligand 1 Positive, ERBB2 Gene Mutation, ESR2 Positive, Hepatitis C RNA Positive, Features, Cascade, Type 1, Zero, Positive Laboratory Test Result, Paired Box 8 Gene Rearrangement, LCAM Gene Mutation, l35Dd, Expressed, ER-Beta Positive, E-Cadherin Gene Mutation, HRAS Gene Mutation, Arc-1 Gene Mutation, Harvey Rat Sarcoma Viral Oncogene Homolog Gene Mutation, N-SAM Gene Mutation, N-SAM Gene Rearrangement, CD274 Positive, VAL, BRAF Rearrangement, CDH1 Gene Mutation, Ordered, Step Unit of Distance, KRAS-2 Gene Mutation, PDL1 Positive, Covalent, Anti-HBs Positive, Gene, KIT Positive, c-erbB2 Gene Activation, cycE, Anti-HBc Antibody Positive, TERT Promoter Mutation, KAL2 Gene Mutation, l(2)br37, ECT1 Gene Rearrangement, CYCLE, Anoctamin-1 Positive, FGFR-3 Gene Mutation, polypeptide chain, Fp Positive, Fibroblast Growth Factor Receptor 1 Gene Rearrangement, OGD Gene Mutation, Anti-HBcAb Positive, Anti-Hepatitis B Virus Surface Antibody Positive, Hep C RNA Positive, HIV test positive, CD274 Antigen Positive, Epithelial Gene Mutation, MET Proto-Oncogene, Erb-B2 Receptor Tyrosine Kinase Gene Mutation, BFGFR Gene Rearrangement, CYCE, pattern, distribution, SWS Gene Mutation, TAOS2 Positive, DmelCG3938, Fibroblast Growth Factor Receptor 3 Gene Mutation, CyclE, Cadherin 1, ORDER, E-Cadherin (Epithelial) Gene Mutation, HER2/neu Gene Mutation, 3938, BRCA1 Associated Protein 1 Gene Mutation, v-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog Positive, Methylguanine-DNA Methyltransferase Gene Promoter Methylation, l(2)k05007, Neuroblastoma RAS Viral Oncogene Homolog Gene Mutation, H-ras Gene Mutation, dm-cycE, ETV Gene Rearrangement, Positive Lymph Node, CD332 Gene Rearrangement, C-H-RAS Gene Mutation, Cascade Device, Ets Variant Gene Family Rearrangement, site, HER2 Gene Amplification, OGD Gene Rearrangement, LT (less than), Characteristics, KAL2 Gene Rearrangement, Behaviors, Anti-Hepatitis C Virus Antibody Positive, SDH1 Positive, CTNNB Gene Mutation, progesterone receptor positive, RASH1 Gene Mutation, behaviour, relational structural quality, ER Alpha Positive, Possess, UCHL2 Gene Mutation, RAD54L Gene Mutation, FORMER, GNA-11 Gene Mutation, Regulatory, CEK Gene Rearrangement, Anti-Hepatitis B Virus Core Antibody Positive, protein complex, Hepatitis C Antibody Positive, Loss of Chromosomes 1p/19q, No Activity Time, ESTRR Positive, K-SAM Gene Rearrangement, Order, Protein Functional Component, Characteristic, del(1p/19q), natural protein, NR3A2 Positive, Fibroblast Growth Factor Receptor 3 Gene Rearrangement, MGMT Gene Promoter Methylation, Covalent Interaction, Protein, sequence, TMEM16A Positive, CyeE, ESRA Positive, Catenin Beta-1 Gene Mutation, MGMT Methylation, AR Positive, ERBB2 Mutation, STEPS, Acceptance, ETV Family Rearrangement, Argument, Hepatitis C Virus Antibody Positive, FMS-Like Tyrosine Kinase 2 Gene Mutation, Beta-Catenin Gene Mutation, GA11 Gene Mutation, PARM, HIV Positivity, Mast/Stem Cell Growth Factor Receptor Kit Positive, Paired Box Gene 8 Gene Rearrangement, TP2 Promoter Mutation, Protein Component, l(2)35Dd, ORAOV2 Positive, FGFR-2 Gene Mutation, parameter, Calcium-Dependent Adhesion Protein, Protein Gene Products, BAP1 Mutation, c-K-ras Gene Mutation, behavioural response to stimulus, Change, Population Measure, FGFR-1 Gene Mutation, HBs Antigen Positive, CD274 Molecule Positive, CG3938, Mitochondrial Positive, GTPase Gene Mutationextent, Signal Transduction Systems, Signal Transductions, Sectors, Public Sectors, PLXN5, cycline, MTOC attachment site, conformation, region or site annotation, Processes, DmcyclinE, PFD, fond, Receptor-Mediated, number, Nl1, Gene, Signal Transduction System, PLEXIN-B1, cycE, Copyrights, protein, CycEI, protein-containing complex, gonadotropin-independent female-limited sexual precocity, presence, phosphorylation, l(2)br37, mccune-albright syndrome, SeP, CYCLE, cdi7, Receptor Mediated Signal Transduction, Albright's disease, Signal Transduction, protein polypeptide chains, CEH, Ccne, cyclinE, polypeptide chain, Cdi7, CDI7, Gene Products, NEPII, NL1, NL2, SEH, Public Enterprise, Cell Signaling, protein aggregate, Enterprises, MAS, Sep, SEP, signal transduction by protein phosphorylation, CG2916, positional, proportion, CYCE, pattern, distribution, DmelCG3938, CyclE, absent from organism, Public Domains, Signal, 3938, Pathways, proteins, Signal Pathways, behavioral response to stimulus, DmcycE, Public Enterprises, Signal Transduction Pathway, sEP, l(2)k05007, signalling pathway, dm-cycE, Abstract, SELP, signal transduction by cis-phosphorylation, site, s, Signal Transduction Pathways, Transductions, Behaviors, Enterprise, Signal Pathway, behaviour, relational structural quality, ratio, single-organism behavior, Pathway, Process, completeness, protein complex, Proteins, polyostotic fibrous dysplasia, Phosphorylations, signal transduction by conformational transition, Receptor-Mediated Signal Transductions, Mell1, dephosphorylation, somatic, Cyc E, br37, results, signal transduction by trans-phosphorylation, Acceptance Processes, sep5, signaling cascade, Acceptance Process, count in organism, l(2)k02514, macrophage activation syndrome, native protein, DmCycE, BG:DS07108.3, natural protein, MMEL2, Public, Public Domain, Receptor-Mediated Signal Transduction, Systems, Protein, Domains, sequence, CyeE, signalling cascade, l(2)05206, Transduction, region, Domain, reactive hemophagocytic lymphohistiocytosis, Data Base, Acceptance, absence, l(2)k02602, positional polypeptide feature, System, DmelCG2916, proportionality, l(2)35Dd, rate, mosaic, POFD, primary structure of sequence macromolecule, McCune Albright syndrome, Protein Gene Products, requirements, D-CycE, Gene Proteins, Sector, l35Dd, behavioural response to stimulus, signaling pathway, microtubule organising centre attachment site, quotient, Eph2, Public., quantitative, Feedbacks, CG3938, NEP2, presence or absence in organismsignal transduction by protein phosphorylation, Signal Transduction Systems, Signal Transductions, Pathway, System, Receptor-Mediated, Phosphorylations, signal transduction by conformational transition, Signal, Receptor-Mediated Signal Transductions, Pathways, Signal Transduction System, Signal Pathways, Signal Transduction Pathway, Structure, phosphorylation, signal transduction by trans-phosphorylation, Receptor Mediated Signal Transduction, Signal Transduction, signaling cascade, signalling pathway, Structural, signaling pathway, Receptor-Mediated Signal Transduction, Systems, signal transduction by cis-phosphorylation, Signal Transduction Pathways, Transductions, signalling cascade, Cell Signaling, Transduction, Signal Pathway, requirements.falseOrtega2006 - bistability from double phosphorylation in signal transduction
Ortega2006 - bistability from double
phosphorylation in signal transduction
This model is described in the article:
Bistability from double
phosphorylation in signal transduction. Kinetic and structural
requirements.
Ortega F, Garcés JL, Mas F,
Kholodenko BN, Cascante M.
FEBS J. 2006 Sep; 273(17):
3915-3926
Abstract:
Previous studies have suggested that positive feedback loops
and ultrasensitivity are prerequisites for bistability in
covalent modification cascades. However, it was recently shown
that bistability and hysteresis can also arise solely from
multisite phosphorylation. Here we analytically demonstrate
that double phosphorylation of a protein (or other covalent
modification) generates bistability only if: (a) the two
phosphorylation (or the two dephosphorylation) reactions are
catalyzed by the same enzyme; (b) the kinetics operate at least
partly in the zero-order region; and (c) the ratio of the
catalytic constants of the phosphorylation and
dephosphorylation steps in the first modification cycle is less
than this ratio in the second cycle. We also show that
multisite phosphorylation enlarges the region of kinetic
parameter values in which bistability appears, but does not
generate multistability. In addition, we conclude that a
cascade of phosphorylation/dephosphorylation cycles generates
multiple steady states in the absence of feedback or
feedforward loops. Our results show that bistable behavior in
covalent modification cascades relies not only on the structure
and regulatory pattern of feedback/feedforward loops, but also
on the kinetic characteristics of their component proteins.
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2015-05-222010-07-292010-08-10BIOMD000000025816934033CHEBI:16541MODEL1008100000BIOMD0000000258GO:0006468C00017C00562131567