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P38MAPK-dependent phosphorylation and degradation of SRC-3/AIB1 and RARalpha-mediated transcription

Maurizio Giannì1, Edoardo Parrella, Ivan Raska

  • 1Laboratorio di Biologia Molecolare, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italia.

The EMBO Journal
|February 4, 2006
PubMed

Insights

Retinoic acid receptors (RARs) control gene expression. Phosphorylation of coactivator SRC-3 by p38MAPK initially aids RARalpha activation but later inhibits transcription by promoting SRC-3 degradation.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Cell Signaling

Background:

  • Nuclear retinoic acid receptors (RARs) regulate gene expression through interactions with coregulators.
  • Ligand binding and phosphorylation are key regulatory processes in RAR activity.

Purpose of the Study:

  • To investigate the role of p38MAPK-mediated phosphorylation of the p160 coactivator SRC-3 in retinoic acid (RA)-dependent RARalpha gene activation.
  • To elucidate the dual role of SRC-3 phosphorylation in modulating RARalpha transcriptional activity.

Main Methods:

  • Studied RA-dependent activation of RARalpha isotype.
  • Investigated phosphorylation of p160 coactivator SRC-3 by p38MAPK.
  • Analyzed the impact of p38MAPK inhibition on RARalpha-mediated transcription and cell differentiation.

Main Results:

  • SRC-3 phosphorylation by p38MAPK initially facilitates RARalpha-target gene activation by altering coactivator-receptor interaction dynamics.
  • Subsequently, SRC-3 phosphorylation promotes its degradation, leading to transcriptional inhibition.
  • Inhibition of p38MAPK significantly enhances RARalpha-mediated transcription and RA-induced cell differentiation.
  • SRC-3 phosphorylation and degradation are specific to RARalpha complexes, suggesting an RAR isotype-dependent phosphorylation code.

Conclusions:

  • RARalpha transcriptional activity is regulated by SRC-3 through a mechanism involving coordinated phosphorylation and degradation events.
  • These events are fine-tuned by retinoic acid (RA) and p38MAPK signaling.
  • The RAR isotype dictates a phosphorylation code influencing coactivator accessibility to kinases like p38MAPK.

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