Transforming growth factor-beta receptor-associated protein 1 is a Smad4 chaperone

Members of the transforming growth factor-beta (TGF-beta) superfamily signa l through unique cell membrane receptor serine-threonine kinases to activat e downstream targets. TRAP1 is a previously described 96-kDa cytoplasmic pr otein shown to bind to TGF-beta receptors and suggested to play a role in T GF-beta signaling. We now fully characterize the binding properties of TRAP 1, 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 sig nal 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 in hibit TGF-beta signaling and diminish the interaction of Smad4 with Smad2. These are the first data to identify a specific molecular chaperone for Sma d4, suggesting a model in which TRAP1 brings Smad4 into the vicinity of the receptor complex and facilitates its transfer to the receptor-activated Sm ad proteins.