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.
Laboratory of Cell Regulation and Carcinogenesis and Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
J U
JU
Wurthner
D B
DB
Frank
A
A
Felici
H M
HM
Green
Z
Z
Cao
M D
MD
Schneider
J G
JG
McNally
R J
RJ
Lechleider
A B
AB
Roberts
D028341:Activins; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000939:Epitopes / Q000378:metabolism; D017353:Gene Deletion; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006801:Humans; D015151:Immunoblotting; D007265:Inhibins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051899:Smad2 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000939:Epitopes; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008164:Luminescent Proteins; D018832:Molecular Chaperones; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C111893:TGFBRAP1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D028341:Activins; D049452:Green Fluorescent Proteins; D007265:Inhibins