Mammaliancellmotilityrequiresactinpolymerizationinthedirectionofmovementtochangemembraneshapeandextendcytoplasmintolamellipodia.Thepolymerizationofactintodrivecellmovementalsoinvolvesbranchingofactinfilamentsintoanetworkorientedwiththegrowingendsofthefibersnearthecellmembrane.ManipulationofthisprocesshelpsbacterialikeSalmonellagainentryintocellstheyinfect.TwooftheproteinsinvolvedintheformationofYbranchesandincellmotilityareArp2andArp3,bothmembersofalargemultiproteincomplexcontainingseveralotherpolypeptidesaswell.TheArp2/3complexislocalizedattheYbranchjunctionandinducesactinpolymerization.Activityofthiscomplexisregulatedbymultipledifferentcellsurfacereceptorsignalingsystems,activatingWASP,andArp2/3inturntocausechangesincellshapeandcellmotility.WaspanditscousinWave-1interactwiththeArp2/3complexthroughthep21componentofthecomplex.ThecrystalstructureoftheArp2/3complexhasrevealedfurtherinsightsintothenatureofhowthecomplexworks.ActivationbyWave-1,anothermemberoftheWASPfamily,alsoinducesactinalterationsinresponsetoRac1signalsupstream.Wave-1isheldinaninactivecomplexinthecytosolthatisactivatedtoallowWave-1toassociatewithArp2/3.WhileWASPisactivatedbyinteractionwithCdc42,Wave-1,isactivatedbyinteractionwithRac1andNck.Wave-1activationbyRac1andNckreleasesWave-1withHspc300toactivateactinYbranchingandpolymerizationbyArp2/3.Differentmembersofthisgenefamilymayproducedifferentactincytoskeletalarchitectures.TheimmunologicaldefectsassociatedwithmutationoftheWASPgene,theWiskott-AldrichsyndromeforwhichWASPwasnamed,indicatestheimportanceofthissystemfornormalcellularfunction.

Contributor:KosiGramatikoff,PhD

REFERENCES:CoryGO,RidleyAJ.Cellmotility:brakingWAVEs.Nature.2002Aug15;418(6899):732-3.Noabstractavailable.Eden,S.,etal.(2002)MechanismofregulationofWAVE1-inducedactinnucleationbyRac1andNck.Nature418(6899),790-3FaletH,HoffmeisterKM,NeujahrR,HartwigJH.NormalArp2/3complexactivationinplateletslackingWASp.Blood.2002Sep15;100(6):2113-22.Kreishman-DeitrickM,RosenMK,Kreishman-DeltrickM.Ignitionofacellularmachine.NatCellBiol.2002Feb;4(2):E31-3.Noabstractavailable.Machesky,L.M.,Insall,R.H.(1998)Scar1andtherelatedWiskott-Aldrichsyndromeprotein,WASP,regulatetheactinCytoskeletonthroughtheArp2/3complex.CurrBiol8(25),1347-56Robinson,R.C.etal.(2001)CrystalstructureofArp2/3complex.Science294(5547),1679-84WeedsA,YeohS.Structure.ActionattheY-branch.Science.2001Nov23;294(5547):1660-1.Noabstractavailable.

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