Smad2 functions as a co-activator of canonical Wnt/beta-catenin signaling pathway independent of Smad4 through histone acetyltransferase activity of p300.
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.
Hirota
Morihisa
M
Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, USA.
Watanabe
Kazuhide
K
Hamada
Shin
S
Sun
Youping
Y
Strizzi
Luigi
L
Mancino
Mario
M
Nagaoka
Tadahiro
T
Gonzales
Monica
M
Seno
Masaharu
M
Bianco
Caterina
C
Salomon
David S
DS
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*
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