Smad6 as a transcriptional corepressor

Smad6 and Smad7, a subgroup of Smad proteins, antagonize the signals elicit ed by transforming growth factor-beta, These two Smads, induced by transfor ming growth factor-beta or bone morphogenetic protein (BMP) stimulation, fo rm stable associations with their activated type I receptors, blocking phos phorylation of receptor-regulated Smads in the cytoplasm, Here we show that Smad6 interacts with homeobox (Hox) c-8 as a transcriptional corepressor, inhibiting BMP signaling in the nucleus. The interaction between Smad6 and Hoxc-8 was identified by a yeast two-hybrid approach and further demonstrat ed by co immunoprecipitation assays in cells. Gel shift assays show that Sm ad6, but not Smad7, interacts with both Hoxc-8 and Hoxa-9 as a heterodimer when binding to DNA. More importantly, the Smad6-Hoxc-8 complex inhibits in teraction of Smad1 with Hoxc-8- and Smad1-induced transcription activity. T hese data indicate that Smad6 interacts with Hox transcription factors as p art of the negative feedback circuit in the BMP signaling pathway.