Sensitivity Analysis of Intracellular Signaling Pathway Kinetics Predicts Targets for Stem Cell Fate Control 英文参考文献.docVIP

SensitivityAnalysisofIntracellular SignalingPathwayKineticsPredictsTargets forStemCellFateControl Alborz Mahdavi1,2,Ryan E.Davey2,Patrick Bhola2,Ting Yin1,Peter W. Zandstra1,2* 1Department ofChemical Engineering andAppliedChemistry,Universityof Toronto, Toronto, Ontario, Canada, 2Institute ofBiomaterialsandBiomedical Engineering, UniversityofToronto,Toronto,Ontario,Canada Directingstemcellfaterequiresknowledgeofhowsignalingnetworksintegratetemporallyandspatiallysegregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3) pathway kinetics, a signaling network involved in embryonic stem cell (ESC) self-renewal. Our analysis identifiednovelpathwayresponses;forexample,overexpressionofthereceptorglycoprotein-130resultsinreduced pathwayactivationandincreasedESCdifferentiation.Weusedasystematicinsilicoscreentoidentifynoveltargets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation) is regulated by balancing the activation state of a distributedsetofparametersincludingnuclearexportofStat3,nuclearphosphataseactivity,inhibitionbysuppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand deliverystrategythatmaximizessignalingactivationandleadstoenhancedESCself-renewal. Citation:MahdaviA,DaveyRE,BholaP,YinT,ZandstraPW(2007)Sensitivityanalysisofintracellularsignalingpathwaykineticspredictstargetsforstemcellfatecontrol.PLoS ComputBiol3(7):e130.doi:10.1371/journal.pcbi.0030130 signalingiscontrolledpresentsachallengewhichmaybebest addressedbymathematicalmodeling[30]. Introduction Self-renewal is one of the de?ning characteristics of embryonicstemcells(ESCs)[1].Thisfatechoiceisin?uenced by ligand–receptor-mediated activation of intracellular sig- naling pathways. Signi?cant work is being done to under- stand the signalin