Human BAMBI Cooperates with Smad7 to Inhibit Transforming Growth Factor-β Signaling*

Transforming growth factor β (TGF-β) and related growth factors are essential regulators of embryogenesis and tissue homeostasis. The signaling pathways mediated by their receptors and Smad proteins are precisely modulated by various means. Xenopus BAMBI (bone morphogenic protein (BMP) and activin membrane-bound inhibitor) has been shown to function as a general negative regulator of TGF-β/BMP/activin signaling. Here, we provide evidence that human BAMBI (hBAMBI), like its Xenopus homolog, inhibits TGF-β- and BMP-mediated transcriptional responses as well as TGF-β-induced R-Smad phosphorylation and cell growth arrest, whereas knockdown of endogenous BAMBI enhances the TGF-β-induced reporter expression. Mechanistically, in addition to interfering with the complex formation between the type I and type II receptors, hBAMBI cooperates with Smad7 to inhibit TGF-β signaling. hBAMBI forms a ternary complex with Smad7 and the TGF-β type I receptor ALK5/TβRI and inhibits the interaction between ALK5/TβRI and Smad3, thus impairing Smad3 activation. These findings provide a novel insight to understand the molecular mechanism underlying the inhibitory effect of BAMBI on TGF-β signaling