RB1CC1 protein positively regulates transforming growth factor-beta signaling through the modulation of Arkadia E3 ubiquitin ligase activity.
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.
Mesh Terms:
Animals, DNA-Binding Proteins, Gene Expression Regulation, Gene Knockdown Techniques, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Nuclear Proteins, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Signal Transduction, Transforming Growth Factor beta, Ubiquitin-Protein Ligases
Animals, DNA-Binding Proteins, Gene Expression Regulation, Gene Knockdown Techniques, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Nuclear Proteins, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Signal Transduction, Transforming Growth Factor beta, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: Sep. 16, 2011
PubMed ID: 21795712
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