The TGFβ Pathway Interactome ENHANCED.PDF

This SnapShot originally appeared in the April 18,2008 issue of Cell.SnapShot:The TGF Pathway InteractomeIan W.Taylor and Jeffrey L.WranaSamuel Lunenfeld Research Institute and Department of Molecular Genetics,University of Toronto,Toronto,ON M5G 1X5,Canada Transforming Growth Factor (TGF)was first identified for its ability to induce anchorage-independent growth(Roberts et al.,1981)and is the founding member of the largest fam-ily of secreted morphogens in mammals.The TGF family is divided into distinct classes,based on biological function,that include activins,inhibins,bone morphogenetic proteins(BMPs),and Mullerian-inhibiting substance(MIS)(Laiho and Keski-Oja,1992).Signaling by all TGF family members occurs via transmembrane serine/threonine kinases that upon ligand binding form a heteromeric complex of type II and type I receptors(reviewed in Shi and Massague,2003).In the eponymous TGF pathway this occurs via ligand-induced cooperative assembly of the receptor complex,thus allowing the kinase domain of the type II receptor to phosphorylate the type I receptor,as well as other receptor-bound com-ponents.In the canonical pathway,signaling to the transcriptional machinery is transduced by a unique family of intracellular signaling mediators called Smads(Heldin et al.,1997).Phosphorylation of the type I receptor by the type II kinase thus activates Smad signaling,likely by creating a docking site on the type I kinase for binding of the receptor-regulated class of Smads(R-Smad2/3)(Huse et al.,2001).Once bound to the type I receptor,R-Smads are phosphorylated on the last two serines at a conserved carboxy-terminal SSXS motif.This induces dissociation from the receptor complex,drives assembly of R-Smads into a complex with a second class of Smads,the so-called co-Smad(Smad4),and leads to the nuclear accumulation of heteromeric Smad complexes.In the nucleus,Smads regulate transcription of TGF target genes by interacting with a broad range of DNA-binding partners.One transcriptional target of Smad signaling is a third class of Smads,called the inhibitory Smads(I-Smads)of which Smad7 is a potent inhibitor of TGF signaling(Hayashi et al.,1997;Nakao et al.,1997).Smad7 acts in a negative feedback loop to inhibit Smad activation and recruits the E3 ubiquitin ligases,Smad Ubiquitin Regulatory Factors 1/2(Smurf 1/2),to the receptor complex to mediate receptor turnover(reviewed in Izzi and Attisano,2004).In this SnapShot we show that the core components of this canonical TGF-Smad pathway are embedded within a large network of physical protein-protein interactions that play key roles in mediating the complex biology of TGF.At the level of the receptor,TGF binds accessory receptors(such as TGFBRIII and endoglin)to facilitate ligand binding and other intracellular partners involved in non-Smad signaling pathways(top left nodes).Trafficking of TGF receptors has emerged as a key regulator of Smad signaling(Le Roy and Wrana,2005)and is reflected in the association of the receptors with numerous components of the trafficking system(green nodes).The receptor complex and Smurfs also bind Par6 and other components of the polarity complex(blue nodes),thereby regulating apical-basal polarity during epithelial-to-mesenchymal transition.In the nucleus,the Smad 2/3/4 complex associates with a broad range of DNA-binding partners(orange nodes),which recruit Smads to regulatory elements of target genes.Smads in turn regulate transcriptional output by coupling to core transcriptional cofactors(e.g.,p300,ARC105,BRG1,etc.;pink nodes).Cell type specificity in Smad DNA-binding partner expression and the role of many of these Smad partners in other signaling pathways is proposed to confer tremendous diversity in the TGF transcriptional response(Feng and Derynck,2005).The Smad pathway also directly engages in signal transduction crosstalk with other well-described pathways(e.g.,AKT1 and ERK;yellow nodes).All interactions in this diagram are taken from literature-curated sources.PubMed IDs for the literature sources of each interaction as well as a Cytoscape compatible file of these interactions can be found at http:/dynactome.mshri.on.ca/tgfb/TGFbeta%20interactome%20040108.xls.RefeRencesFeng,X.H.,and Derynck,R.(2005).Specificity and versatility in tgf-beta signaling through Smads.Annu.Rev.Cell Dev.Biol.21,659693.Hayashi,H.,Abdollah,S.,Qiu,Y.,Cai,J.,Xu,Y.Y.,Grinnell,B.W.,Richardson,M.A.,Topper,J.N.,Gimbrone,M.A.,Jr.,Wrana,J.L.,et al.(1997).The MAD-related protein Smad7 as-sociates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling.Cell 89,11651173.Heldin,C.H.,Miyazono,K.,and ten Dijke,P.(1997).TGF-beta signalling from cell membrane to nucleus through SMAD proteins.Nature 390,465471.Huse,M.,Muir,T.W.,Xu,L.,Chen,Y.G.,Kuriyan,J.,and Massague,J.(2001).The TGF beta receptor activation process:An inhibitor-to substrate-binding switch.Mol.Cell 8,671682.Izzi,L.,and Attisano,L.(2004).Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation.Oncogene 23,20712078.Laiho,M.,and Keski-Oja,J.(1992).Transforming growth factors-beta as regulators of cellular growth and phenotype.Crit.Rev.Oncog.3,126.Le Roy,C.,and Wrana,J.L.(2005).Clathrin-and non-clathrin-mediated endocytic regulation of cell signalling.Nat.Rev.Mol.Cell Biol.6,112126.Nakao,A.,Afrakhte,M.,Moren,A.,Nakayama,T.,Christian,J.L.,Heuchel,R.,Itoh,S.,Kawabata,M.,Heldin,N.E.,Heldin,C.H.,et al.(1997).Identification of Smad7,a TGFbeta-inducible antagonist of TGF-beta signalling.Nature 389,631635.Roberts,A.B.,Anzano,M.A.,Lamb,L.C.,Smith,J.M.,and Sporn,M.B.(1981).New class of transforming growth factors potentiated by epidermal growth factor:Isolation from non-neoplastic tissues.Proc.Natl.Acad.Sci.USA 78,53395343.Shi,Y.,and Massague,J.(2003).Mechanisms of TGF-beta signaling from cell membrane to the nucleus.Cell 113,685700.