Oneofthecentralfeaturesofmitoticcelldivisionistheformationofthespindlethatsegregateschromosomesintoeachdaughtercell.Chromosomesarenotjustpassengersalongforaridewiththespindle,butactiveparticipantsinthenucleationandstABIlizationofspindlemicrotubulesintheirnearvicinity.Theras-likeGTPaseRanthatregulatesnucleocytoplasmictransportthroughthenuclearporecomplex(NPC)duringinterphase(See“RoleofRaninNucleocytoplasmicTransport”Pathway)alsoregulatestheformationofthemitoticspindle.Ranplaysasimilarroleineachoftheseprocesses,regulatingdownstreamsignalingpathwaysinadifferentialmannerbasedonwhetherGDPorGTPisbound.LikeotherGTPases,theinherentGTPaseactivityofRanisregulatedbyGTPaseactivatingproteins(GAPs)andbyexchangefactors.AnexchangefactorthatstimulatesnucleotideexchangebytheRanGTPaseisRCC1,whichbindstochromatininbothinterphaseandmitosis.WhileRCC1helpsRANdrivetransportbetweenthenucleusandcytoplasmduringinterphase,thelocalizationofRCC1onchromatinduringmitosislocalizesRan-GTPnearchromosomes,localizingmicrotubuleformationintheseregions.Ran-BP1andRan-GAP1stimulateGTPhydrolysisbyRan,convertingitbacktoRan-GDPfurtherawayfromchromosomes.Asterpromotingactivities(APA)andtheimportin-alphaandimportin-betaproteinsinvolvedwithRaninnucleocytoplasmictransportarealsoinvolvedinmitoticspindleformation.Asterpromotingactivitiesstabilizemicrotubulesduringspindleformation,butbindingofimportinstoAPAneutralizestheiractivityinformingmicrotubules.TheimportinsbindtoAPAwhenfarfromthechromosomes,whereRan-GDPpredominates,butRan-GTPnearchromosomescausesimportinstoreleaseAPAfactorsincludingTpx2andNuMa,allowingthemtostimulatemicrotubuleformation.Tpx2interactswiththemicrotubulemotorproteinXklp2andalsoactivatestheAuroraAmitotickinase,requiredforspindleformation.Inadditiontoregulatingspindleformation,Ranmayalsohelpreformthenuclearenvelopeaftercelldivisionandmayuseasimilarmechanismtoregulateothercellularprocesses.

Contributor:GlennCrostonPhD

REFERENCES:DassoM.RunningonRan:nucleartransportandthemitoticspindle.Cell2001Feb9;104(3):321-4GrussOJetal.Chromosome-inducedmicrotubuleassemblymediatedbyTPX2isrequiredforspindleformationinHeLacells.NatCellBiol2002Nov;4(11):871-9KahanaJA,ClevelandDW.Cellcycle.Someimportinnewsaboutspindleassembly.Science2001Mar2;291(5509):1718-9MooreWetal.TargetingofRCC1tochromosomesisrequiredforpropermitoticspindleassemblyinhumancells.CurrBiol2002Aug20;12(16):1442-7TsaiMYetal.ARansignallingpathwaymediatedbythemitotickinaseAuroraAinspindleassembly.NatCellBiol2003Mar;5(3):242-8WieseCetal.Roleofimportin-betaincouplingRantodownstreamtargetsinmicrotubuleassembly.Science2001Jan26;291(5504):653-6

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