title: Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signaling.
abstract: Transforming growth factor-beta (TGF-beta) signaling is controlled by a variety of regulators that target either signaling receptors or activated Smad complexes. Among the negative regulators, Smad7 antagonizes TGF-beta signaling mainly through targeting the signaling receptors, whereas SnoN and c-Ski repress signaling at the transcriptional level through inactivation of Smad complexes. We previously found that Arkadia is a positive regulator of TGF-beta signaling that induces ubiquitin-dependent degradation of Smad7 through its C-terminal RING domain. We report here that Arkadia induces degradation of SnoN and c-Ski in addition to Smad7. Arkadia interacts with SnoN and c-Ski in their free forms as well as in the forms bound to Smad proteins, and constitutively down-regulates levels of their expression. Arkadia thus appears to effectively enhance TGF-beta signaling through simultaneous down-regulation of two distinct types of negative regulators, Smad7 and SnoN/c-Ski, and may play an important role in determining the intensity of TGF-beta family signaling in target cells.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nagano
authors.forename: Konstantinos J
authors.initials: KJ
authors.lastname: Mavrakis
authors.forename: Kian Leong
authors.initials: KL
authors.lastname: Lee
authors.forename: Tomoko
authors.initials: T
authors.lastname: Fujii
authors.forename: Daizo
authors.initials: D
authors.lastname: Koinuma
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sase
authors.forename: Keiko
authors.initials: K
authors.lastname: Yuki
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Isogaya
authors.forename: Masao
authors.initials: M
authors.lastname: Saitoh
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.forename: Vasso
authors.initials: V
authors.lastname: Episkopou
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C060614:SKI protein, human; C427283:Rnf111 protein, mouse; D044767:Ubiquitin-Protein Ligases