Operating Regimes of Signaling Cycles Statics, Dynamics, and Noise Filtering 英文参考文献.docVIP

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Operating Regimes of Signaling Cycles Statics, Dynamics, and Noise Filtering 英文参考文献.doc

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Operating Regimes of Signaling Cycles Statics, Dynamics, and Noise Filtering 英文参考文献

OperatingRegimesofSignalingCycles: Statics,Dynamics,andNoiseFiltering Carlos Gomez-Uribe1,2,George C.Verghese2,Leonid A.Mirny1* 1Harvard–MITDivisionofHealthSciencesandTechnology,MassachusettsInstituteofTechnology,Cambridge,Massachusetts,UnitedStatesofAmerica,2Departmentof ElectricalEngineeringandComputerScience,MassachusettsInstituteofTechnology,Cambridge,Massachusetts,UnitedStatesofAmerica A ubiquitous building block of signaling pathways is a cycle of covalent modification (e.g., phosphorylation and dephosphorylationinMAPKcascades).Ourpaperexploresthekindofinformationprocessingandfilteringthatcanbe accomplished by this simple biochemical circuit. Signaling cycles are particularly known for exhibiting a highly sigmoidal(ultrasensitive)input–outputcharacteristicinacertainsteady-stateregime.Here,wesystematically study thecycle’ssteady-statebehavioranditsresponsetotime-varyingstimuli.Wedemonstratethatthecyclecanactually operateinfourdifferentregimes,eachwithitsspecificinput–outputcharacteristics.Theseresultsareobtainedusing the total quasi–steady-state approximation, which is more generally valid than the typically used Michaelis-Menten approximationforenzymaticreactions.Weinvokeexperimentaldatathatsuggestthepossibilityofsignalingcycles operatinginoneofthenewregimes.Wethenconsiderthecycle’sdynamicbehavior,whichhassofarbeenrelatively neglected. We demonstrate that the intrinsic architecture of the cycles makes them act—in all four regimes—as tunable low-pass filters, filtering out high-frequency fluctuations or noise in signals and environmental cues. Moreover,thecutofffrequencycanbeadjustedbythecell.Numericalsimulationsshowthatouranalyticalresultshold wellevenfornoiseoflargeamplitude.Wesuggestthatnoisefilteringandtunabilitymakesignalingcyclesversatile componentsofmoreelaboratecell-signalingpathways. Citation:Gomez-UribeC,VergheseGC,MirnyLA(2007)Operatingregimesofsignalingcycles:Statics,dynamics,andnoisefiltering.PLoSComputBiol3(12):e246.doi:10. 1371/journal.p