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

Zhenghong Lin,Chan Gao,Yuanheng Ning,Xi He,Wei Wu,Ye-Guang Chen

doi:10.1074/jbc.m804039200

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.

Highlights

Wnt signaling is initiated by binding to its seven-transmembrane receptor, Frizzled (Fzd),2 and single-span transmembrane coreceptor low density lipoprotein receptor-related protein 5 and 6 (LRP5/6) [1,2,3,4]
BAMBI Promotes Wnt Signaling—As the ␤-catenin/T-cell factor (TCF) complex induces the expression of BAMBI in colorectal and hepatocellular tumor cells [17], we attempted to investigate whether BAMBI has an effect on Wnt signaling by using the Wnt-responsive lymphoid enhancer-binding factor (LEF)-luciferase reporter
We demonstrated that BAMBI enhances the expression of the Wnt-responsive reporters LEF-luciferase and Topflash-luciferase, but not the control Fopflash-luciferase, in the presence or absence of Wnt-1

Summary

Introduction

Wnt signaling is initiated by binding to its seven-transmembrane receptor, Frizzled (Fzd),2 and single-span transmembrane coreceptor low density lipoprotein receptor-related protein 5 and 6 (LRP5/6) [1,2,3,4]. BAMBI Promotes Wnt Signaling—As the ␤-catenin/TCF complex induces the expression of BAMBI in colorectal and hepatocellular tumor cells [17], we attempted to investigate whether BAMBI has an effect on Wnt signaling by using the Wnt-responsive LEF-luciferase reporter. We generated an siRNA construct against BAMBI (si-BAMBI) and examined its effectiveness on Wnt-1-induced expression of LEF-luciferase in HEK293T cells that express BAMBI protein (data not shown).

Results

Conclusion