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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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COS Cells
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Chlorocebus aethiops
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Down-Regulation / drug effects
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Down-Regulation / physiology
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HeLa Cells
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Mice
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Protein Binding / drug effects
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Protein Binding / physiology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Smad7 Protein / genetics
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Smad7 Protein / metabolism
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Transcription, Genetic / drug effects
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Transcription, Genetic / physiology
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta / pharmacology
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Ubiquitin / genetics
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Ubiquitin / metabolism*
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Ubiquitin-Protein Ligases
Substances
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins
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SKIL protein, human
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SMAD7 protein, human
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Smad7 Protein
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Smad7 protein, mouse
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Transforming Growth Factor beta
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Ubiquitin
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SKI protein, human
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Rnf111 protein, mouse
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Ubiquitin-Protein Ligases