Roles Of BAMBI Protein In Regulating TGF-β Signaling And Wnt Signaling

Transforming growth factorβ(TGF-β) and related growth factors are essential regulators of embryogenesis and tissue homeostasis. The signaling pathway mediated by their receptors and Smad proteins is precisely modulated by various means. BAMBI has been shown to negatively regulate the signaling activity of TGF-β, BMP, and activin in Xenopus embryos. Here, we provide evidence that human BAMBI, like its Xenopus homolog, inhibits the transcriptional response of TGF-βsignaling, suggesting an evolutionally conserved activity of BAMBI. We further show that human BAMBI can interact with TGF-βreceptors as well as the inhibitory Smad7. Immunoprecipitation assay revealed that BAMBI not only impairs the heterocomplex formation of TGF-βtype I and type II receptors, but also enhance the binding of Smad7 to TGF-βtype I receptor. Finally, we demonstrate that human BAMBI can attenuate TGF-β-induced cell growth and cell migration.The Wnt/Wingless pathway plays a pivotal role in embryonic development and adult homeostasis by regulating cell fate, proliferation, and differentiation, and it is aberrantly reactivated in various human cancers. Recently BAMBI had been identified as a target ofβ-catenin, which could directly induce its expression in colorectal and hepatocellular tumor cells. However, whether and how this protein regulates Wnt signaling remains a complete mystery. In this study, we firstly demonstrated that BAMBI can promote Wnt signaling by reporter assays. Blocking the expression of BAMBI protein by small interfering RNA can decrease the signaling activity of Wnt-responsive reporters. Furthermore, we also show that it can enhance the association of Wnt signaling receptor and Dvl-2, leading to the increase of Wnt signaling. Finally we show that BAMBI can induce Wnt target gene expression such as c-myc and cyclin D1 and promote the cell growth.BAMBI, a pseudoreceptor of TGF-βsignaling, can be induced by both TGF-βand Wnt signaling pathway and it also exerts an effect on their downstream signaling events, thus playing an important role in the regulation of cell growth and pathogenesis.