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Evidence for a role of MSK1 in transforming growth factor-beta-mediated responses through p38alpha and Smad signaling

Lucile Abécassis1, Edith Rogier, Aimé Vazquez

  • 1INSERM U542, Bâtiment Lavoisier, Hôpital Paul Brousse, 14 Avenue Paul Vaillant Couturier, 94807 Villejuif, France.

The Journal of Biological Chemistry
|May 11, 2004
PubMed

Insights

This study reveals how p38 mitogen-activated protein kinase (MAPK) signaling integrates with Smad proteins to regulate transforming growth factor-beta (TGF-beta) responses. It uncovers a nuclear mechanism involving MSK1 kinase in Smad3 coactivator binding and gene activation.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Gene regulation

Background:

  • Smad proteins are key mediators of transforming growth factor-beta (TGF-beta) superfamily signaling.
  • Mitogen-activated protein kinase (MAPK) p38 is a downstream target essential for TGF-beta responses.
  • The precise cross-talk mechanism between p38 and Smad pathways in TGF-beta signaling remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of cross-talk between p38 and Smad signaling pathways in TGF-beta-mediated cellular responses.
  • To investigate the role of p38alpha isoform in Smad3-mediated transcriptional regulation.
  • To identify downstream effectors involved in integrating these signaling cascades.

Main Methods:

  • Utilized inhibition of p38alpha isoform to assess its effect on Smad3-mediated TGF-beta responses.
  • Examined the impact of p38 inhibition on TGF-beta-induced phosphorylation of MSK1 kinase.
  • Employed dominant-interfering mutants of MSK1 to study its role in Smad3-p300 coactivator binding.

Main Results:

  • Inhibition of p38alpha suppressed Smad3's ability to mediate TGF-beta-induced transcriptional responses.
  • p38 inhibition blocked TGF-beta-mediated phosphorylation of MSK1 kinase, a key chromatin remodeling enzyme.
  • Expression of dominant-interfering MSK1 mutants disrupted Smad3 binding to p300 in response to TGF-beta.

Conclusions:

  • A novel mechanism for integrating Smad and p38 signaling pathways in the nucleus has been identified.
  • MSK1 kinase acts as a crucial link, mediating the interaction between p38 activity and Smad3 coactivator recruitment.
  • This cross-talk is essential for the activation of gene expression in response to TGF-beta signaling.

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