ThisSnapShotoriginallyappearedintheApril18,2008issueofCell.SnapShot:TheTGFβPathwayInteractomeIanW.TaylorandJeffreyL.WranaSamuelLunenfeldResearchInstituteandDepartmentofMolecularGenetics,UniversityofToronto,Toronto,ONM5G1X5,CanadaTransformingGrowthFactorβ(TGFβ)wasfirstidentifiedforitsabilitytoinduceanchorage-independentgrowth(Robertsetal.,1981)andisthefoundingmemberofthelargestfam-ilyofsecretedmorphogensinmammals.TheTGFβfamilyisdividedintodistinctclasses,basedonbiologicalfunction,thatincludeactivins,inhibins,bonemorphogeneticproteins(BMPs),andMullerian-inhibitingsubstance(MIS)(LaihoandKeski-Oja,1992).SignalingbyallTGFβfamilymembersoccursviatransmembraneserine/threoninekinasesthatuponligandbindingformaheteromericcomplexoftypeIIandtypeIreceptors(reviewedinShiandMassague,2003).IntheeponymousTGFβpathwaythisoccursvialigand-inducedcooperativeassemblyofthereceptorcomplex,thusallowingthekinasedomainofthetypeIIreceptortophosphorylatethetypeIreceptor,aswellasotherreceptor-boundcom-ponents.Inthecanonicalpathway,signalingtothetranscriptionalmachineryistransducedbyauniquefamilyofintracellularsignalingmediatorscalledSmads(Heldinetal.,1997).PhosphorylationofthetypeIreceptorbythetypeIIkinasethusactivatesSmadsignaling,likelybycreatingadockingsiteonthetypeIkinaseforbindingofthereceptor-regulatedclassofSmads(R-Smad2/3)(Huseetal.,2001).OnceboundtothetypeIreceptor,R-Smadsarephosphorylatedonthelasttwoserinesataconservedcarboxy-terminalSSXSmotif.Thisinducesdissociationfromthereceptorcomplex,drivesassemblyofR-SmadsintoacomplexwithasecondclassofSmads,theso-calledco-Smad(Smad4),andleadstothenuclearaccumulationofheteromericSmadcomplexes.Inthenucleus,SmadsregulatetranscriptionofTGFβtargetgenesbyinteractingwithabroadrangeofDNA-bindingpartners.OnetranscriptionaltargetofSmadsignalingisathirdclassofSmads,calledtheinhibitorySmads(I-Smads)ofwhichSmad7isapotentinhibitorofTGFβsignaling(Hayashietal.,1997;Nakaoetal.,1997).Smad7actsinanegativefeedbacklooptoinhibitSmadactivationandrecruitstheE3u...
