Whiletranscriptionalregulationisoftenviewedasthemostprevalentwayextracellularsignalstoregulategeneexpression,post-transcriptionalregulationofsplicing,RNAstABIlity,andtranslationarealsoregulatedbyextracellularsignals.Sam68,amemberofafamilyofRNA-bindingproteinscalledSTARproteins,mediatesalternativesplicinginresponsetoextracellularsignals,suchasalteredsplicingofCD44inresponsetophorbolestertreatmentofTcells.RNAbindingandactivityofSAM68isregulatedbyupstreamsignalsthroughphosphorylationandmodulatingofitsinteractionwithotherproteins,itselfandwithRNA.PhorbolestertreatmentofTcellsstimulatestheras/Mapkinasepathway,activatingErkandphosphorylationofSam68,inducingalternativesplicingofCD44andperhapsothercellularRNAtargets.Sam68islocalizedinthenucleustoaspecificsubstructurecalledtheSam68/SLMNuclearBodies,colocalizingwithsplicingfactorsandhelpingtolinkperhapssignaltransductionwithRNAprocessing.Sam68hasbeensuggestedtoplayaroleinavarietyofpathways,includinginsulinsignalingandHIVgeneexpression,substitutingfortheactivityofviralRevprotein,andtoberegulatedbyargininemethylationaswellasphosphorylation.InadditiontotheroleofSam68regulatingposttranscriptionalgeneexpression,Sam68alsointeractswithtranscriptionfactorssuchasCBPandappearstoregulategeneexpression.Sam68alsoappearstoplayaroleincellcycleprogressionthroughinfluencingRNAprocessing.DuringmitosisSAM68istyrosinephosphorylatedandassociatedwithSrc.TheinteractionofSam68withRNAisrepressedbythisphosphorylation,whereasinteractionofSam68withRas-GAPisstimulatedbyphosphorylation.Sam68appearstobedownregulatedintumorsandtransformedcellsanditsexpressionisreducedduringmitosis,suggestingitinhibitsproliferation.TheRNAbindingdomaininSam68,calledaKHdomain,isabsentinaspliceisoformthatisexpressedincellsthatdisplaycontactinhibitionofcellulargrowth.Sam68withtheKHdomainappearsinsomesettingstostimulatetheG1/Stransition,whileblockingmitosisinsomereports.

Contributor:GlennCroston,PhD

REFERENCES:BarlatIetal.AroleforSam68incellcycleprogressionantagonizedbyasplicedvariantwithintheKHdomain.JBiolChem.1997Feb7;272(6):3129-32.ChenTetal.Self-associationofthesingle-KH-domainfamilymembersSam68,GRP33,GLD-1,andQk1:roleoftheKHdomain.MolCellBiol.1997Oct;17(10):5707-18.CoyleJHetal.Sam68enhancesthecytoplasmicutilizationofintron-containingRNAandisfunctionallyregulatedbythenuclearkinaseSik/BRK.MolCellBiol.2003Jan;23(1):92-103.DerryJJetal.Sik(BRK)phosphorylatesSam68inthenucleusandnegativelyregulatesitsRNAbindingability.MolCellBiol.2000Aug;20(16):6114-26.GuitardEetal.Sam68isaRas-GAP-associatedproteininmitosis.BiochemBiophysResCommun.1998Apr17;245(2):562-6.HongWetal.PhysicalandfunctionalinteractionbetweenthetranscriptionalcofactorCBPandtheKHdomainproteinSam68.MolCancerRes.2002Nov;1(1):48-55.ItohMetal.IdentificationofcellularmRNAtargetsforRNA-bindingproteinSam68.NucleicAcidsRes.2002Dec15;30(24):5452-64.LiJetal.DirectparticipationofSam68,the68-kilodaltonSrc-associatedproteininmitosis,intheCRM1-mediatedRevnuclearexportpathway.JVirol.2002Aug;76(16):8374-82.MatterNetal.Signal-dependentregulationofsplicingviaphosphorylationofSam68.Nature.2002Dec12;420(6916):691-5ResnickRJetal.PhosphorylationoftheSrcsubstrateSam68byCdc2duringmitosis.Oncogene.1997Sep;15(11):1247-53.Sanchez-MargaletV,NajibS.Sam68isadockingproteinlinkingGAPandPI3Kininsulinreceptorsignaling.MolCellEndocrinol.2001Oct25;183(1-2):113-21.ShenZetal.EvidenceforSH3domaindirectedbindingandphosphorylationofSam68bySrc.Oncogene.1999Aug19;18(33):4647-53.

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