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

Estrogen is a growth factor that stimulates cell proliferation. The effects of estrogen are mediated through the estrogen receptors, ER alpha and ER beta, which function as ligand-induced transcription factors and belong to the nuclear receptor superfamily. On the other hand, TGF-beta 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/ER alpha and TGF-beta/Smad signaling, whose molecular mechanisms remain to be determined. Here, we show that ER alpha inhibits TGF-beta signaling by decreasing Smad protein levels. ER alpha-mediated reductions in Smad levels did not require the DNA binding ability of ER alpha, implying that ER alpha opposes the effects of TGF-beta via a novel non-genomic mechanism. Our analysis revealed that ER alpha 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 ER alpha