Selective Inhibitory Effects of Smad6 on Bone Morphogenetic Protein Type I Receptors

Kouichiro Goto, Yuto Kamiya, Takeshi Imamura, Kohei Miyazono, Keiji Miyazawa
2007 Journal of Biological Chemistry  
The inhibitory Smads, Smad6 and Smad7, play pivotal roles in negative regulation of transforming growth factor-␤ (TGF-␤) family signaling as feedback molecules as well as mediators of cross-talk with other signaling pathways. Whereas Smad7 acts as a ubiquitous inhibitor of Smad signaling, Smad6 has been shown to effectively inhibit bone morphogenetic protein (BMP) signaling but only weakly TGF-␤/activin signaling. In the present study, we have found that Smad6 inhibits signaling from the
more » ... ing from the activin receptor-like kinase (ALK)-3/6 subgroup in preference to that from the ALK-1/2 subgroup of BMP type I receptors. The difference is attributable to the interaction of Smad6 with these BMP type I receptors. The amino acid residues responsible for Smad6 sensitivity of ALK-3 were identified as Arg-238, Phe-264, Thr-265, and Ala-269, which map to the N-terminal lobe of the ALK-3 kinase domain. Although Smad6 regulates BMP signaling through multiple mechanisms, our findings suggest that interaction with type I receptors is a critical step in the function of Smad6.
doi:10.1074/jbc.m702100200 pmid:17493940 fatcat:zg7n42kgkzc3ldmpz3u5hip5my