Transforming growth factor-beta receptor-associated protein 1 is a Smad4 chaperone.
Members of the transforming growth factor-beta (TGF-beta) superfamily signal through unique cell membrane receptor serine-threonine kinases to activate downstream targets. TRAP1 is a previously described 96-kDa cytoplasmic protein shown to bind to TGF-beta receptors and suggested to play a role in TGF-beta signaling. We now fully characterize the binding properties ... of TRAP1, and show that it associates strongly with inactive heteromeric TGF-beta and activin receptor complexes and is released upon activation of signaling. Moreover, we demonstrate that TRAP1 plays a role in the Smad-mediated signal transduction pathway, interacting with the common mediator, Smad4, in a ligand-dependent fashion. While TRAP1 has only a small stimulatory effect on TGF-beta signaling in functional assays, deletion constructs of TRAP1 inhibit TGF-beta signaling and diminish the interaction of Smad4 with Smad2. These are the first data to identify a specific molecular chaperone for Smad4, suggesting a model in which TRAP1 brings Smad4 into the vicinity of the receptor complex and facilitates its transfer to the receptor-activated Smad proteins.
Mesh Terms:
Activins, Animals, COS Cells, Carrier Proteins, Cell Line, Cytoplasm, DNA-Binding Proteins, Epitopes, Gene Deletion, Genes, Reporter, Green Fluorescent Proteins, Humans, Immunoblotting, Inhibins, Intracellular Signaling Peptides and Proteins, Ligands, Luminescent Proteins, Mice, Microscopy, Fluorescence, Models, Biological, Molecular Chaperones, Plasmids, Precipitin Tests, Protein Binding, Protein Biosynthesis, Protein Structure, Tertiary, Signal Transduction, Smad2 Protein, Smad4 Protein, Trans-Activators, Transcription, Genetic, Transfection, Transforming Growth Factor beta
Activins, Animals, COS Cells, Carrier Proteins, Cell Line, Cytoplasm, DNA-Binding Proteins, Epitopes, Gene Deletion, Genes, Reporter, Green Fluorescent Proteins, Humans, Immunoblotting, Inhibins, Intracellular Signaling Peptides and Proteins, Ligands, Luminescent Proteins, Mice, Microscopy, Fluorescence, Models, Biological, Molecular Chaperones, Plasmids, Precipitin Tests, Protein Binding, Protein Biosynthesis, Protein Structure, Tertiary, Signal Transduction, Smad2 Protein, Smad4 Protein, Trans-Activators, Transcription, Genetic, Transfection, Transforming Growth Factor beta
J. Biol. Chem.
Date: Jun. 01, 2001
PubMed ID: 11278302
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