title: Smad2 functions as a co-activator of canonical Wnt/beta-catenin signaling pathway independent of Smad4 through histone acetyltransferase activity of p300.
abstract: Both canonical Wnt/beta-catenin and TGFbeta/Smad signaling pathways coordinately regulate pattern formation during embryogenesis as well as tumor progression. Evidence of cross-talk between these two pathways has been reported. Here we demonstrated that the Activin-like kinase 4 (Alk4)/Smad2 pathway facilitates the transcriptional activity of the oncogenic Wnt/beta-catenin/Tcf4 pathway through a novel Smad4-independent mechanism. Upon activation, Smad2 physically interacted with Tcf4, beta-catenin and the co-activator p300 to enhance transcriptional activity of beta-catenin/Tcf4 through the histone acetyltransferase activity of p300. Transactivation by Smad2 was independent of a Smad-binding element (SBE) and Smad4. Indeed, the enhancement of beta-catenin/Tcf4 transcriptional activity by activated Smad2 was negatively regulated by the presence of Smad4. Moreover, a tumor-derived missense mutant of Smad2, lacking the ability to bind to Smad4 was still able to enhance the Tcf4 transcriptional reporter in the presence of beta-catenin and Tcf4. Our findings suggest that Smad2 may function as an activator of canonical Wnt/beta-catenin/Tcf4 signaling through a SBE/Smad4-independent pathway.
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, USA.
authors.forename: Morihisa
authors.initials: M
authors.lastname: Hirota
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Watanabe
authors.forename: Shin
authors.initials: S
authors.lastname: Hamada
authors.forename: Youping
authors.initials: Y
authors.lastname: Sun
authors.forename: Luigi
authors.initials: L
authors.lastname: Strizzi
authors.forename: Mario
authors.initials: M
authors.lastname: Mancino
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Nagaoka
authors.forename: Monica
authors.initials: M
authors.lastname: Gonzales
authors.forename: Masaharu
authors.initials: M
authors.lastname: Seno
authors.forename: Caterina
authors.initials: C
authors.lastname: Bianco
authors.forename: David S
authors.initials: DS
authors.lastname: Salomon
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D002460:Cell Line; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D008957:Models, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D051899:Smad2 Protein; D051901:Smad4 Protein; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D051176:beta Catenin; D051548:Histone Acetyltransferases; D050880:p300-CBP Transcription Factors; D030201:Activin Receptors, Type I