Seeonlineversionforlegendandreferences.378Cell133,April18,2008©2008ElsevierInc.DOI10.1016/j.cell.2008.04.007SnapShot:TheTGFβPathwayInteractomeIanW.TaylorandJeffreyL.WranaSamuelLunenfeldResearchInstituteandDepartmentofMolecularGenetics,UniversityofToronto,Toronto,ONM5G1X5,Canada378.e1Cell133,April18,2008©2008ElsevierInc.DOI10.1016/j.cell.2008.04.007SnapShot:TheTGFβPathwayInteractomeIanW.TaylorandJeffreyL.WranaSamuelLunenfeldResearchInstitute,Toronto,ONM5G1X5,CanadaTransformingGrowthFactorβ(TGFβ)wasfirstidentifiedforitsabilitytoinduceanchorage-independentgrowth(Robertsetal.,1981)andisthefoundingmemberofthelargestfamilyofsecretedmorphogensinmammals.TheTGFβfamilyisdividedintodistinctclasses,basedonbiologicalfunction,thatincludeactivins,inhibins,bonemorphogeneticproteins(BMPs),andMullerian-inhibitingsubstance(MIS)(LaihoandKeski-Oja,1992).SignalingbyallTGFβfamilymembersoccursviatransmembraneserine/threoninekinasesthatuponligandbindingformaheteromericcomplexoftypeIIandtypeIreceptors(reviewedinShiandMassague,2003).IntheeponymousTGFβpathwaythisoccursvialigand-inducedcooperativeassemblyofthereceptorcomplex,thusallowingthekinasedomainofthetypeIIreceptortophosphorylatethetypeIreceptor,aswellasotherreceptor-boundcomponents.Inthecanonicalpathway,signalingtothetranscriptionalmachineryistransducedbyauniquefamilyofintracellularsignalingmediatorscalledSmads(Heldinetal.,1997).PhosphorylationofthetypeIreceptorbythetypeIIkinasethusactivatesSmadsignaling,likelybycreatingadockingsiteonthetypeIkinaseforbindingofthereceptor-regulatedclassofSmads(R-Smad2/3)(Huseetal.,2001).OnceboundtothetypeIreceptor,R-Smadsarephosphory-latedonthelasttwoserinesataconservedcarboxy-terminalSSXSmotif.Thisinducesdissociationfromthereceptorcomplex,drivesassemblyofR-SmadsintoacomplexwithasecondclassofSmads,theso-calledco-Smad(Smad4),andleadstothenuclearaccumulationofheteromericSmadcomplexes.Inthenucleus,SmadsregulatetranscriptionofTGFβtargetgenesbyinteractingwithabroadrangeofDNA-bindingpartners.Onetra...
