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

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Abstract
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.