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


ABSTRACT: 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.

SUBMITTER: Felici A 

PROVIDER: S-EPMC202370 | biostudies-literature | 2003 Sep

REPOSITORIES: biostudies-literature

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

Felici Angelina A   Wurthner Jens U JU   Parks W Tony WT   Giam Louise Ruh-yu LR   Reiss Michael M   Karpova Tatiana S TS   McNally James G JG   Roberts Anita B AB  

The EMBO journal 20030901 17


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  ...[more]

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