The Pseudoreceptor BMP and Activin Membrane-bound Inhibitor Positively Modulates Wnt/β-Catenin Signaling

Abstract

The canonical Wnt/beta-catenin pathway plays a pivotal role in regulating embryogenesis and tumorigenesis by promoting cell proliferation. BAMBI (BMP and activin membrane-bound inhibitor) has previously been shown to negatively regulate the signaling activity of transforming growth factor-beta, activin, and BMP and was identified as a target of beta-catenin in colorectal and hepatocellular tumor cells. In this study, we provide evidence that BAMBI can promote the transcriptional activity of Wnt/beta-catenin signaling. Overexpression of BAMBI enhances the expression of Wnt-responsive reporters, whereas knockdown of endogenous BAMBI attenuates them. Accordingly, BAMBI also promotes the nuclear translocation of beta-catenin. BAMBI interacts with Wnt receptor Frizzled5, coreceptor LRP6, and Dishevelled2 and increases the interaction between Frizzled5 and Dishevelled2. Finally we show that BAMBI promotes the expression of c-myc and cyclin D1 and increases Wnt-promoted cell cycle progression. Altogether, our data indicate that BAMBI can function as a positive regulator of the Wnt/beta-catenin pathway to promote cell proliferation.