Estrogen inhibits transforming growth factor β signaling by promoting Smad2/3 degradation

Ichiaki Ito, Aki Hanyu, Mitsutoshi Wayama, Natsuka Goto, Yoko Katsuno, Shohei Kawasaki, Yuka Nakajima, Masashi Kajiro, Yoko Komatsu, Akiko Fujimura, Ryuichi Hirota, Akiko Murayama, Keiji Kimura, Takeshi Imamura, Junn Yanagisawa

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Estrogen is a growth factor that stimulates cell proliferation. The effects of estrogen are mediated through the estrogen receptors,ERα andERβ, which function as ligand-induced transcription factors and belong to the nuclear receptor superfamily. On the other hand, TGF-β acts as a cell growth inhibitor, and its signaling is transduced by Smads. Although a number of studies have been made on the cross-talk between estrogen/ERα and TGF-β/Smad signaling, whose molecular mechanisms remain to be determined. Here, we show that ERα inhibits TGF-β signaling by decreasing Smad protein levels. ERα-mediated reductions in Smad levels did not require the DNA binding ability of ERα, implying that ERα opposes the effects of TGF-β via a novel non-genomic mechanism. Our analysis revealed that ERα formed a protein complex with Smad and the ubiquitin ligase Smurf, and enhanced Smad ubiquitination and subsequent degradation in an estrogen-dependent manner. Our observations provide new insight into the molecular mechanisms governing the non-genomic functions of ERα.

Original languageEnglish (US)
Pages (from-to)14747-14755
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number19
DOIs
StatePublished - May 7 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Ito, I., Hanyu, A., Wayama, M., Goto, N., Katsuno, Y., Kawasaki, S., Nakajima, Y., Kajiro, M., Komatsu, Y., Fujimura, A., Hirota, R., Murayama, A., Kimura, K., Imamura, T., & Yanagisawa, J. (2010). Estrogen inhibits transforming growth factor β signaling by promoting Smad2/3 degradation. Journal of Biological Chemistry, 285(19), 14747-14755. https://doi.org/10.1074/jbc.M109.093039