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

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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
Pages (from-to)1632-1641
Number of pages10
JournalCellular Signalling
Volume20
Issue number9
DOIs
Publication statusPublished - 01-09-2008

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All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Hirota, M., Watanabe, K., Hamada, S., Sun, Y., Strizzi, L., Mancino, M., Nagaoka, T., Gonzales, M., Seno, M., Bianco, C., & Salomon, D. S. (2008). Smad2 functions as a co-activator of canonical Wnt/β-catenin signaling pathway independent of Smad4 through histone acetyltransferase activity of p300. Cellular Signalling, 20(9), 1632-1641. https://doi.org/10.1016/j.cellsig.2008.05.003