Abstract
SARA, an early endosomal protein, plays a key role in TGFβ signalling, as it presents SMAD2 and SMAD3 for phosphorylation by the activated TGFβ receptors. Here, we show that ERBIN is a new SARA-interacting protein that can be recruited by SARA to early endosomes. ERBIN was recently shown to bind and segregate phosphorylated SMAD2 and SMAD3 (SMAD2/3) in the cytoplasm, thereby inhibiting SMAD2/3-dependent transcription. SARA binds to ERBIN using a new domain, which we have called the ERBID (ERBIN-binding domain), whereas ERBIN binds to SARA using a domain (amino acids 1208-1265) that also interacts with SMAD2 and SMAD3, which we have called the SSID (SARA- and SMAD-interacting domain). We additionally show that SARA competes with SMAD2/3 for binding to ERBIN. In agreement, overexpression of SARA or the ERBID peptide reverses the inhibitory effect of ERBIN on SMAD2/3-dependent transcription. Taken together, these data suggest that the response of cells to TGFβ and activin A can be influenced by the relative concentrations of SARA, ERBIN and SMAD2/3.
@ 2011. Published by The Company of Biologists Ltd
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activins / metabolism
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Line
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Cell Nucleus / metabolism
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Genes, Reporter
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Humans
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Luciferases, Renilla / biosynthesis
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Luciferases, Renilla / genetics
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Mice
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Peptide Fragments / metabolism
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Transport
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RNA Interference
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Response Elements
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Serine Endopeptidases / chemistry
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism*
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Smad2 Protein / metabolism*
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Smad3 Protein / metabolism*
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Transcriptional Activation
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Transforming Growth Factor beta / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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ERBIN protein, human
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Intracellular Signaling Peptides and Proteins
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Peptide Fragments
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SMAD2 protein, human
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SMAD3 protein, human
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Smad2 Protein
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Smad3 Protein
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Transforming Growth Factor beta
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activin A
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Activins
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Luciferases, Renilla
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ZFYVE16 protein, human
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Serine Endopeptidases