Smad2 functions as a co-activator of canonical Wnt/β-catenin signaling pathway independent of Smad4 through histone acetyltransferase activity of p300

Morihisa Hirota, Kazuhide Watanabe*, Shin Hamada, Youping Sun, Luigi Strizzi, Mario Mancino, Tadahiro Nagaoka, Monica Gonzales, Masaharu Seno, Caterina Bianco, David S. Salomon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Both canonical Wnt/β-catenin and TGFβ/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/β-catenin/Tcf4 pathway through a novel Smad4-independent mechanism. Upon activation, Smad2 physically interacted with Tcf4, β-catenin and the co-activator p300 to enhance transcriptional activity of β-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 β-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 β-catenin and Tcf4. Our findings suggest that Smad2 may function as an activator of canonical Wnt/β-catenin/Tcf4 signaling through a SBE/Smad4-independent pathway.

Original languageEnglish (US)
Pages (from-to)1632-1641
Number of pages10
JournalCellular Signalling
Volume20
Issue number9
DOIs
StatePublished - Sep 2008

Keywords

  • Activin
  • Beta-catenin
  • Smads
  • TGF-beta
  • Tcf/Lef
  • Wnt

ASJC Scopus subject areas

  • Cell Biology

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