2009
Four‐dimensional dynamics of MAPK information‐processing systems
Kholodenko BN, Birtwistle MR. Four‐dimensional dynamics of MAPK information‐processing systems. WIREs Mechanisms Of Disease 2009, 1: 28-44. PMID: 20182652, PMCID: PMC2826817, DOI: 10.1002/wsbm.16.Peer-Reviewed Original ResearchConceptsMultiple target proteinsMyriad of stimuliCell surface receptorsMAPK cascadeActive kinasePhosphorylation signalsProtein phosphorylationCellular outcomesCytosolic localizationProtein kinaseEndocytotic traffickingPlasma membraneProtein activityTarget proteinsMembrane confinementXenopus eggsToggle switchKinaseMolecular motorsIntracellular gradientsSpatio-temporal guidanceLarge cellsFour-dimensional dynamicsPhosphorylationTraffickingMolecular Dynamics Simulations Reveal that Tyr-317 Phosphorylation Reduces Shc Binding Affinity for Phosphotyrosyl Residues of Epidermal Growth Factor Receptor
Suenaga A, Hatakeyama M, Kiyatkin AB, Radhakrishnan R, Taiji M, Kholodenko BN. Molecular Dynamics Simulations Reveal that Tyr-317 Phosphorylation Reduces Shc Binding Affinity for Phosphotyrosyl Residues of Epidermal Growth Factor Receptor. Biophysical Journal 2009, 96: 2278-2288. PMID: 19289054, PMCID: PMC2717265, DOI: 10.1016/j.bpj.2008.11.018.Peer-Reviewed Original ResearchConceptsSrc homology 2Epidermal growth factor receptorGrowth factor receptorPhospho-tyrosine binding (PTB) domainsLinker regionFull-length ShcPhospho-tyrosine residuesKey conformational changesFactor receptorShc interactionTyr-317Protein ShcTyrosine kinase receptorsPhosphorylated ShcPTB domainRas-mitogenHomology 2Phosphorylation resultsPhosphotyrosyl peptidesProtein kinaseTyrosine phosphorylationBinding domainsSubsequent phosphorylationPhosphotyrosyl residuesShc
2004
Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades
Markevich N, Hoek J, Kholodenko B. Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. Journal Of Cell Biology 2004, 164: 353-359. PMID: 14744999, PMCID: PMC2172246, DOI: 10.1083/jcb.200308060.Peer-Reviewed Original ResearchConceptsExtracellular signal-regulated kinaseMultisite phosphorylationProtein kinase cascadeBistable switchSignal-regulated kinaseKinase cascadeMAPK cascadeWidespread mechanismDifferent kinasesSame phosphataseProtein kinasePositive feedback loopProtein activityDephosphorylation reactionsCovalent modificationKinaseMAPK phosphorylationFeedback regulationPhosphorylationKinetic propertiesPhosphataseFeedback loopCascade
2000
Diffusion control of protein phosphorylation in signal transduction pathways
KHOLODENKO B, BROWN G, HOEK J. Diffusion control of protein phosphorylation in signal transduction pathways. Biochemical Journal 2000, 350: 901-907. PMID: 10970807, PMCID: PMC1221325, DOI: 10.1042/bj3500901.Peer-Reviewed Original ResearchConceptsProtein phosphorylationProtein kinasePhosphorylation fluxProtein diffusionSignal transduction pathwaysProtein phosphataseSpherical cellsTransduction pathwaysDifferent cellular geometriesCellular locationPlasma membranePlanar membranesKinaseCell membraneCellular geometryProtein diffusion coefficientsPhosphatasePhosphorylationCell centerProteinMembraneCellsSpatial gradientsCytoplasmPathwayNegative feedback and ultrasensitivity can bring about oscillations in the mitogen‐activated protein kinase cascades
Kholodenko B. Negative feedback and ultrasensitivity can bring about oscillations in the mitogen‐activated protein kinase cascades. The FEBS Journal 2000, 267: 1583-1588. PMID: 10712587, DOI: 10.1046/j.1432-1327.2000.01197.x.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinaseMAPK cascadeProtein kinaseProtein phosphorylation cascadeSlow protein diffusionNegative feedback loopPhosphorylation cascadeSignal transductionFeedback loopCellular targetsProtein diffusionMAPK phosphorylationPhosphorylation levelsCell typesIntracellular wavesKinasePhosphorylationCascadeFunctional organizationUltrasensitivityRecent kinetic dataExternal stimuliTransductionTotal proteinCytoplasm
1999
Spatial gradients of cellular phospho‐proteins
Brown G, Kholodenko B. Spatial gradients of cellular phospho‐proteins. FEBS Letters 1999, 457: 452-454. PMID: 10471827, DOI: 10.1016/s0014-5793(99)01058-3.Peer-Reviewed Original ResearchConceptsCellular signalingProtein kinaseDifferent cellular geometriesCellular locationPlasma membranePhosphorylated formPlanar membranesProtein diffusionPhosphatase activityKinaseCellular geometryProtein diffusion coefficientsSpatial gradientsSpherical cellsProteinMembraneSuch gradientsCellsSignalingCytoplasmPhosphataseImportant implicationsGradientPotential size