TLP, a novel modulator of TGF-beta signaling, has opposite effects on Smad2- and Smad3-dependent signaling

Transforming growth factor-beta (TGF-beta) 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-beta and activin type II receptors, but interacts with the common-mediator SMAD4 only in the presence of TGF-beta/activin signaling. Overexpression of TLP represses the ability of TGF-beta 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-beta transcriptional responses in both normal and pathophysiology.