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

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