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

J U Wurthner1, D B Frank, A Felici

  • 1Laboratory of Cell Regulation and Carcinogenesis and Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.

The Journal of Biological Chemistry
|March 30, 2001
PubMed

Insights

Heat shock protein TRAP1 binds inactive TGF-beta receptors and Smad4, acting as a chaperone to facilitate Smad4 transfer and regulate transforming growth factor-beta signaling pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Transforming growth factor-beta (TGF-beta) superfamily proteins signal via receptor serine-threonine kinases.
  • TRAP1 is a cytoplasmic protein previously linked to TGF-beta receptor binding.

Purpose of the Study:

  • To fully characterize the binding properties of TRAP1.
  • To elucidate TRAP1's role in TGF-beta and activin signaling pathways.
  • To identify TRAP1 as a molecular chaperone for Smad4.

Main Methods:

  • Protein binding assays to characterize TRAP1 interactions.
  • Functional assays to assess TRAP1's effect on TGF-beta signaling.
  • Analysis of Smad protein interactions using deletion constructs.

Main Results:

  • TRAP1 strongly associates with inactive TGF-beta and activin receptor complexes.
  • TRAP1 is released from receptors upon signaling activation.
  • TRAP1 interacts with Smad4 in a ligand-dependent manner.
  • TRAP1 deletion constructs inhibit TGF-beta signaling and reduce Smad4-Smad2 interaction.

Conclusions:

  • TRAP1 acts as a specific molecular chaperone for Smad4.
  • TRAP1 facilitates Smad4 transfer to receptor-activated Smad proteins.
  • TRAP1 plays a regulatory role in Smad-mediated TGF-beta signal transduction.

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