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RAP250 is a coactivator in the transforming growth factor beta signaling pathway that interacts with Smad2 and Smad3

Per Antonson1, Tomas Jakobsson, Tova Almlöf

  • 1Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Huddinge, Sweden. per.antonson@biosci.ki.se

The Journal of Biological Chemistry
|February 12, 2008
PubMed

Insights

RAP250 acts as a coactivator in transforming growth factor-beta (TGF-beta) signaling by binding Smad2 and Smad3. This interaction bridges TGF-beta and liver X receptors (LXR) pathways, impacting gene expression.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Gene Regulation

Background:

  • RAP250 is a known coactivator for nuclear receptors and transcription factors.
  • Its precise mechanism of action in biological processes requires further elucidation.
  • Understanding RAP250's interactions is key to deciphering its role in cellular signaling.

Purpose of the Study:

  • To identify novel protein partners of RAP250.
  • To investigate the role of RAP250 in transforming growth factor-beta (TGF-beta) signaling.
  • To explore potential cross-talk between TGF-beta and liver X receptor (LXR) signaling pathways mediated by RAP250.

Main Methods:

  • Yeast two-hybrid screening to identify RAP250 interacting proteins.
  • Co-immunoprecipitation assays to confirm protein interactions.
  • Analysis of gene expression in mouse embryonic fibroblasts (MEFs) with and without RAP250.
  • Stimulation assays using TGF-beta and LXR agonists.

Main Results:

  • Smad2 and Smad3 were identified as direct binding partners of RAP250.
  • The interaction involves specific motifs: the second LXXLL motif in RAP250 and the MH2 domain in Smad2/3.
  • RAP250 deficiency in MEFs led to reduced TGF-beta target gene PAI-1 expression.
  • A synergistic effect on LXR target gene ABCG1 expression was observed upon combined TGF-beta and LXR agonist stimulation.

Conclusions:

  • RAP250 functions as a novel coactivator in the TGF-beta signaling pathway, directly interacting with Smad2 and Smad3.
  • The RAP250-Smad2/3 complex serves as a crucial link between TGF-beta and LXR signaling pathways.
  • This cross-talk mechanism influences the expression of key target genes in both pathways.

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