JAK-STAT

SignalingPathwayLigandJAKJanusKinaseRecepterSTATsignaltransducersandactivatorsoftranscriptionDNA（Annu.Rev.Med.2015.66:311-328）LigandReceptorJAKSTATDNACytokinesIL,IFN,Epo,CSF,SCF,LIF,GrowthHermone,TPO,etc.（Annu.Rev.Med.2015.66:311-328）LigandReceptorJAKSTATDNAJAK-bindingreceptorHomodimer：Growthhermones、EPOHeteromultimer：IFN、ILTwoJAK-bindingsubunitFoursite/domainTransmembranedomainJAKbindingbox1/2PhosphorylationtargetingsiteYNCJanusKinase（Justanotherkinase）TYKJAK-1、JAK-2、JAK-3、TYK-2Many-to-manywithligand7JHdomainLigand

ReceptorJAKSTATDNAPhosphotyrosinebinding（SH2）PseudokinasedomainKinasedomainReceptorbindingNCSignaltransducersandactivatorsoftranscriptionSTAT1、STAT2、STAT3、STAT4、

STAT5a/b

、STAT6LatentSTATHomo/HeterodimerImportinα-5、IRF9、RannuclearimportpathwayLigand

ReceptorJAKSTATDNADNAbindingdomainPhosphotyrosinebindingdomain（SH2）TranscriptionalactivationdomainOligomerizationdomainNCYSLigand

ReceptorJAKSTATDNASBS+Targetgene（SOCS,Nmi,Bcl-XL,p21,MYC,NOS2,etc.）GAS:TTCN3GAAorTTCN4GAAISRE:AGTTTNCNTTTCCSIE:TTN6AAJAK-STATSignalingPathwayCellmembraneNuclearmembraneInhibitorSOCS(suppressorsofcytokinesignaling):feedbackloopPIAS(proteininhibitorsofactivatedstats)：STAT；sumoylationPTPKinaseinhibitorydomainPhosphotyrosinebinding（SH2）SOCSboxSAPdomaintargetbindingRINGfingerdomain（SUMOtransfer）Serine/Threonine-richdomain（targetbinding）IllnessSevereCombinedImmunodeficiency(Receptor,JAK3)ImmunodeficiencyandGrowthRetardation(STAT5)Myeloproliferativediseases(MPDs):Polycythemiavera,essentialthrombocytosis,primarymyelofibrosis(JAK2)ApplicationTofacitinibJAK3/1/2RAPsoriasisSpondyloarthropathyTransplantrejection（Annu.Rev.Med.2015.66:311-328）PathwaycrosstalkRTK-likereceptorSHP-2

GRB2

Ras

……JAK

PI3KAtk……SOCS3RAS-GAPRTKSTATRTKRAS/MAPKSTAT-SP

Hedgehog

SignalingPathway×Patched(Ptc)On-state：GliAOff-state：GliRHedgehogApperanceofembryosSonicHHIndianHHDesertHH（NatureReviewsGenetics2,242(April2001)）HHmaturationandsecretionHH-C&HH-N，~25kD&20kDAutoproteolyticSKN:palmitoylated，CysresidueCholesterolDispatch，SCUBE2，cholesterolmotifSoluablemultimerExovesiclesHHPTCSMOGLIHHreceptorcomplexPatched(Ptc)，GAS1，CDO，BOCIgandFNIIIrepeatsPromoteVSinhibitEndocytosis，degradationHHPTCSMOGLIPtctoSmoSmo（smoothened）：GPCROff-state：suppressionofSmoOn-state：activationofSmoHypothesis：PtccontrolstheinfluxortheeffluxofaligandOxysterols：directlybindSmoandpromoteSHHsignalingInhibittheIncreaseoftrafficking&stability(phenomena)Conformationalswitch(phenomena)，PKA，CK1α/2，GPRK2HHPTCSMOGLISmotoGlioff-stateCilia，Kif7SUFUPhosphorylation，PKA，GSK3β，CD1βTrCPSCFE3ubiquitinligasecomplexGliRGli2/3，Gli1（Glioma-associatedoncogene）HHPTCSMOGLIHHPTCSMOGLISmotoGlion-stateBalancechangeGiNophosphorylationandnoproteolysisMechanism

unknownInnucleusTissuerepair:Adultneuralstemcells,severalepithelialtissuesDevelopmentpatterning:limb,neuraltubeTissuegrowth:Cerebellum,retinaOther:Axonguidance,cellularmetabolism,painperceptionPtc，GliSPOPand

CUL3（cullin3）HHPTCSMOGLIUsefultoolsCyclopa