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

Angelina Felici, Jens U. Wurthner, W. Tony Parks, Louise Ruh Yu Giam, Michael Reiss, Tatiana S. Karpova, James G. McNally, Anita B. Roberts*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4465-4477
Number of pages13
JournalEMBO Journal
Volume22
Issue number17
DOIs
StatePublished - Sep 1 2003

Keywords

  • Smad proteins
  • TGF-β receptors
  • TGF-β signaling
  • TRAP-1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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