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Estrogen Inhibits Transforming Growth Factor β Signaling by Promoting Smad2/3 Degradation*

Ichiaki Ito,A. Hanyu,Mitsutoshi Wayama,N. Goto,Yoko Katsuno,S. Kawasaki,Y. Nakajima,M. Kajiro,Yoko Komatsu,A. Fujimura,R. Hirota,A. Murayama,K. Kimura,T. Imamura,J. Yanagisawa

Published 2010 in Journal of Biological Chemistry

ABSTRACT

Estrogen is a growth factor that stimulates cell proliferation. The effects of estrogen are mediated through the estrogen receptors, ERα and ERβ, 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.

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