Transforming growth factor-β (TGF-β) is a multifunctional cytokine signaling to the nucleus through cell surface transmembrane receptor serine/threonine kinases and cytoplasmic effectors, including Smad proteins. We describe a novel modulator of this pathway, TLP (TRAP-1-like protein), which is 25% identical to the previously described Smad4 chaperone, TRAP-1, and shows identical expression patterns in human tissues. Endogenous TLP associates with both active and kinase-deficient TGF-β and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-β/activin signaling. Overexpression of TLP represses the ability of TGF-β to induce transcription from SBE-Luc, a Smad3/4-specific reporter, while it potentiates transcription from ARE-Luc, a Smad2/4-specific reporter. Consistent with this, TLP inhibits the formation of Smad3/4 complexes in the absence of effects on phosphorylation of Smad3, while it affects neither Smad2 phosphorylation nor hetero-oligomerization. We propose that TLP might regulate the balance of Smad2 and Smad3 signaling by localizing Smad4 intracellularly, thus contributing to cellular specificity of TGF-β transcriptional responses in both normal and pathophysiology.
- Smad proteins
- TGF-β receptors
- TGF-β signaling
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)