title: RB1CC1 protein positively regulates transforming growth factor-beta signaling through the modulation of Arkadia E3 ubiquitin ligase activity.
abstract: Transforming growth factor-β (TGF-β) signaling is controlled by a variety of regulators, of which Smad7, c-Ski, and SnoN play a pivotal role in its negative regulation. Arkadia is a RING-type E3 ubiquitin ligase that targets these negative regulators for degradation to enhance TGF-β signaling. In the present study we identified a candidate human tumor suppressor gene product RB1CC1/FIP200 as a novel positive regulator of TGF-β signaling that functions as a substrate-selective cofactor of Arkadia. Overexpression of RB1CC1 enhanced TGF-β signaling, and knockdown of endogenous RB1CC1 attenuated TGF-β-induced expression of target genes as well as TGF-β-induced cytostasis. RB1CC1 down-regulated the protein levels of c-Ski but not SnoN by enhancing the activity of Arkadia E3 ligase toward c-Ski. Substrate selectivity is primarily attributable to the physical interaction of RB1CC1 with substrates, suggesting its role as a scaffold protein. RB1CC1 thus appears to play a unique role as a modulator of TGF-β signaling by restricting substrate specificity of Arkadia.
authors.affiliation: Division of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Daizo
authors.initials: D
authors.lastname: Koinuma
authors.forename: Masahiko
authors.initials: M
authors.lastname: Shinozaki
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nagano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ikushima
authors.forename: Kana
authors.initials: K
authors.lastname: Horiguchi
authors.forename: Kouichiro
authors.initials: K
authors.lastname: Goto
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Chano
authors.forename: Masao
authors.initials: M
authors.lastname: Saitoh
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; D000071183:Autophagy-Related Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071183:Autophagy-Related Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C407704:RB1CC1 protein, human; C428743:Rb1cc1 protein, mouse; C060615:SKIL protein, human; C486157:Skil protein, mouse; D016212:Transforming Growth Factor beta; C060614:SKI protein, human; C486067:RNF111 protein, human; C427283:Rnf111 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases