Transforming Growth Factor-β Receptor-associated Protein 1 Is a Smad4 Chaperone

Abstract

Members of the transforming growth factor-␤ (TGF-␤)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-␤ receptors and suggested to play a role in TGF-␤ signaling. We now fully characterize the binding properties of TRAP1, and show that it associates strongly with inactive heteromeric TGF-␤ 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-␤ signaling in functional assays, deletion constructs of TRAP1 inhibit TGF-␤ 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.

MicroRNA‐181a Regulates Local Immune Balance by Inhibiting Proliferation and Immunosuppressive Properties of Mesenchymal Stem Cells

“…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-b signaling in functional assays, deletion of TRAP1 inhibits TGF-b signaling and impairs the interaction between Smad4 and Smad2 [49]. However, TRAP1 does not affect the phosphorylation of Smad2.…”

Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

“…TGFBRAP1 to VPS39 exchange might further be regulated by proteins such as MON1-CCZ1 (Fig. 6B), which are recruited by CORVET, interact with VPS39, and act as activators of RAB7 (44 -46) and signaling pathways such as the TGF␤ pathway, which has been shown to intersect with TGFBRAP1 and VPS39 function (47)(48)(49).…”

Regulation of cell proliferation by Smad proteins

“…Interestingly, TGF-b receptor-associated protein-1 (TRAP-1) was found to speci®cally interact with Smad4 and to aid in the recruitment of Smad4 to the TGF-b and activin receptor complex (Wurthner et al, 2001). TRAP-1 associates with the inactive TGF-b receptor complex, and upon receptor activation, TRAP-1 dissociates from the receptor complex and associates with Smad4.…”

“…The TRAP-1/Smad4 interaction is transient and disrupted by activated R-Smads. Wurthner et al (2001) suggested that TRAP-1 may function as a chaperone to reduce the auto-inhibitory interactions between N-and C-terminal domains of Smad4 and thereby facilitate the interaction of Smad4 with activated R-Smads.…”