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MED1 phosphorylation promotes its association with mediator: implications for nuclear receptor signaling

Madesh Belakavadi1, Pradeep K Pandey, Ravi Vijayvargia

  • 1Department of Physiology and Biophysics, Robert Wood Johnson Medical School, UMDNJ, Piscataway, NJ 08854, USA.

Molecular and Cellular Biology
|April 9, 2008
PubMed

Insights

Mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) phosphorylation enhances MED1 binding to the Mediator complex. This phosphorylation is stimulated by hormones and is crucial for nuclear hormone receptor coactivator activity and transcription.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Cell Signaling

Background:

  • Mediator is a crucial transcriptional co-activator complex.
  • MED1 is a key subunit that interacts with transcription factors.
  • Mechanisms controlling MED1's association with Mediator are largely unknown.

Purpose of the Study:

  • To investigate the role of MED1 phosphorylation in its association with the Mediator complex.
  • To elucidate the signaling pathways regulating MED1's function.
  • To understand the impact of MED1 phosphorylation on nuclear hormone receptor activity.

Main Methods:

  • In vitro kinase assays using MAPK-ERK and MED1.
  • Co-immunoprecipitation assays to assess protein interactions.
  • Reporter gene assays to measure transcriptional activity.

Main Results:

  • MAPK-ERK directly phosphorylates MED1.
  • Phosphorylation enhances the binding of MED1 to the MED7 subunit of Mediator.
  • Thyroid and steroid hormones stimulate MED1 phosphorylation in cells.
  • MED1 phosphorylation is essential for its coactivator function with nuclear hormone receptors.
  • ERK-mediated phosphorylation of MED1 boosts thyroid hormone receptor-dependent transcription.

Conclusions:

  • ERK phosphorylation of MED1 is a regulatory mechanism controlling its association with the Mediator complex.
  • This pathway links extracellular signals (hormones) to transcriptional regulation via MED1.
  • Phosphorylated MED1 may play a role in a novel feed-forward loop for nuclear hormone signaling.

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