Seeonlineversionforlegendandreferences.SnapShot:Ca2+-Calcineurin-NFATSignalingGeraldR.Crabtree1andStuartL.Schreiber21StanfordUniversitySchoolofMedicine,Stanford,CA94305,USA;2BroadInstituteofHarvardandMIT,Cambridge,MA02142,USA210Cell138,July10,2009©2009ElsevierInc.DOI10.1016/j.cell.2009.06.026210.e1Cell138,July10,2009©2009ElsevierInc.DOI10.1016/j.cell.2009.06.026SnapShot:Ca2+-Calcineurin-NFATSignalingGeraldR.Crabtree1andStuartL.Schreiber21StanfordUniversitySchoolofMedicine,Stanford,CA94305,USA;2BroadInstituteofHarvardandMIT,Cambridge,MA02142,USACa2+-calcineurin-NFATsignalingtransmitssignalstothenucleusfromawidevarietyofreceptorsandisrequiredfordevelopmentaleventsasdiverseasaxonout-growth,cardiacmorphogenesis,lungmorphogenesis,neuralcrestdiversification,epithelialstemcellmaintenance,andimmuneresponses.Thepathwayappearstobeparticularlydedicatedtovertebrate-specificmorphogenicevents,perhapsreflectingitsfirstevolutionaryappearanceinvertebrates.Calcineurin-NFATsignalingisthetargetofthedrugscyclosporinAandFK506andseveralviralimmunemodulators.Inaddition,itsmalfunctionisimplicatedinDown’ssyndrome,diabetes,andcardiachypertrophy.ReceptorsthatinducetheentryofCa2+intothecellresultingintheactivationofcalcineurinphosphataseareshowninthelowerleft.Ca2+bindstotheregulatorysubunitofcalcineurinaswellastocalmodulintoactivatethephosphataseactivityofcalcineurin(StemmerandKlee,1994).TheimmunosuppressivedrugsFK506andcyclosporinAinhibitcalcineurinbybindingfirsttotheabundantintracellularproteins,FKBPandcyclophilin,respectively.Theseproteincomplexesthenbindtocalcineurin,preventingsubstrateaccess(Liuetal.,1991).ThespecificityofthesecalcineurininhibitorsisduetothelargecompositesurfacearisingfromFKBPboundtoFK506(seeinsetstructure)(Griffithetal.,1995)orcyclosporinAboundtocyclophilin.FK506andcyclosporinAarehighlyspecificprobesoftheNFATsignalingpath-wayintissueswheretheconcentrationofcalcineurinislessthantheconcentrationofFKBPorcyclophilin(Graefetal.,2001).Calcineurinremovesseveralphosphateres...
