RB1CC1 protein positively regulates transforming growth factor-beta signaling through the modulation of Arkadia E3 ubiquitin ligase activity

Daizo Koinuma; Masahiko Shinozaki; Yoshiko Nagano; Hiroaki Ikushima; Kana Horiguchi; Kouichiro Goto; Tokuhiro Chano; Masao Saitoh; Takeshi Imamura; Kohei Miyazono; Keiji Miyazawa

doi:10.1074/jbc.M111.227561

RB1CC1 protein positively regulates transforming growth factor-beta signaling through the modulation of Arkadia E3 ubiquitin ligase activity

J Biol Chem. 2011 Sep 16;286(37):32502-12. doi: 10.1074/jbc.M111.227561. Epub 2011 Jul 27.

Authors

Daizo Koinuma¹, Masahiko Shinozaki, Yoshiko Nagano, Hiroaki Ikushima, Kana Horiguchi, Kouichiro Goto, Tokuhiro Chano, Masao Saitoh, Takeshi Imamura, Kohei Miyazono, Keiji Miyazawa

Affiliation

¹ Division of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy-Related Proteins
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Gene Expression Regulation / physiology*
Gene Knockdown Techniques
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Mice
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism*
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Signal Transduction / physiology*
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

Autophagy-Related Proteins
DNA-Binding Proteins
Intracellular Signaling Peptides and Proteins
Nuclear Proteins
Proto-Oncogene Proteins
RB1CC1 protein, human
Rb1cc1 protein, mouse
SKIL protein, human
Skil protein, mouse
Transforming Growth Factor beta
SKI protein, human
RNF111 protein, human
Rnf111 protein, mouse
Ubiquitin-Protein Ligases
Protein-Tyrosine Kinases