title: Selective inhibitory effects of Smad6 on bone morphogenetic protein type I receptors.
abstract: The inhibitory Smads, Smad6 and Smad7, play pivotal roles in negative regulation of transforming growth factor-beta (TGF-beta) 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-beta/activin signaling. In the present study, we have found that Smad6 inhibits signaling 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.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kouichiro
authors.initials: K
authors.lastname: Goto
authors.forename: Yuto
authors.initials: Y
authors.lastname: Kamiya
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D051379:Mice; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism*; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I