ADP-ribosylationfactors(ARFs)are20-kDaguaninenucleotide-bindingproteins,membersoftheRasGTPasesuperfamilythatwereinitiallyrecognizedandpurifiedbecauseoftheirABIlitytostimulatetheADP-ribosyltransferaseactivityofthecholeratoxinAsubunit.WenowknowthattheyarecriticalcomponentsofseveraldifferentvesiculartraffickingpathwaysinalleukaryoticcellsandactivatorsofspecificphospholipaseDs(PLDs)(reviewedinRefs.1?3).ARFinteractswithmanyproteinsandothermoleculesthatregulateitsstateofactivationorareinvolvedinitsintracellularfunction.ArfproteinscyclebetweenGDP-bound,inactiveandGTP-bound,activeforms,andthecyclingisregulatedbyspecificGEPsandGAPs.MembersoftheArfGEPfamilycanbegroupedintotwomajorsubfamiliesonthebasisoftheirsequencesimilaritiesandfunctionaldifferences.Thehigh-molecular-weightArfGEPsubfamilyincludesyeastSec7,Gea1,andGea2,andmammalianBIG1/p200,BIG2,andGBF1,whichallconsistof1,400?2,000aminoacidresidues.ManyArfGAPsaremultidomainproteinsandhavebeenfoundtointeractwithmultiplesignalingmolecules.Forinstance,ASAP1hasaPHdomain,ankyrin(ANK)repeats,proline-richandSrc-homology(SH)3domainsandhasbeenshowntobindPI(4,5)P2,Src,andCrk.PAPa/PAG3,withasimilardomainstructure,bindsphosphoinositides,Src,Pyk,andpaxillin.TheGITsbindbARK,paxillinandtheRac/Cdc42exchangefactorPIX(alsoknownasCool).ASAP-relatedproteins,ARAP1,2and3haveArfGAP,RhoGAP,Ankyrinrepeat,Ras-associating(RA),andfivePHdomains,andthereforehavethepotentialofintegratingfoursignalingpathways.

Contributor:KosiGramatikoff,PhD

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