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Members of the bone morphogenetic protein (BMP) and T-box gene families play several critical roles in the early embryonic development and tissue homeostasis. Although BMP proteins are the upstream regulators of T-box genes, few studies have investigated the molecular mechanisms between these two protein families. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase. Consequently, Smad6 reduces Tbx6-mediated Myf-5 gene activation. Furthermore, specific knockdown of endogenous Smad6 and Smurf1 by small interfering RNA increases the protein levels of Tbx6 and enhance the expression of Tbx6 target genes. Collectively, these findings reveal that Smad6 serves as a critical mediator of BMP signal via a functional interaction with Tbx6, thus regulating the activation of Tbx6 downstream genes during cell differentiation. [ABSTRACT FROM AUTHOR]