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Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic reponses to multiple cellular signaling pathways.

Although several lines of evidence have indicated that the activity of SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM1 could be regulated by phosphorylation, an important question remained as to how different signaling pathways can act through limiting concentrations of the same SRC-3 molecule to exert different physiological functions. Herein, we report the successful identification of six functional in vivo SRC-3 phosphorylation sites. Interestingly, all phosphorylation sites are required for coactivation of estrogen and androgen receptors, but not all sites are required for coactivation of NF-kappaB. Different combinations of site-specific phosphorylations of SRC-3 are required for induction of IL-6 gene expression by TNF-alpha as compared to oncogenic transformation of MEFs. Mechanisms of pathway selectivity involve protein-protein interactions of differentially phosphorylated SRC-3 with downstream transcriptional activators and coactivators. Our results uncovered an additional level of transcriptional regulation whereby specific modulations of SRC-3 phosphorylation allow this coactivator to function as a regulatable integrator for diverse signaling pathways in cells.

Pubmed ID: 15383283

Authors

  • Wu RC
  • Qin J
  • Yi P
  • Wong J
  • Tsai SY
  • Tsai MJ
  • O'Malley BW

Journal

Molecular cell

Publication Data

September 24, 2004

Associated Grants

  • Agency: NIDDK NIH HHS, Id: 5 U19 DK62434-02
  • Agency: NICHD NIH HHS, Id: HD07857
  • Agency: NICHD NIH HHS, Id: HD08818

Mesh Terms

  • Acetyltransferases
  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Fibroblasts
  • Genome
  • Glutathione
  • HeLa Cells
  • Histone Acetyltransferases
  • Humans
  • Mice
  • Nuclear Receptor Coactivator 3
  • Oncogene Proteins
  • Phosphorylation
  • Precipitin Tests
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Retroviridae
  • Signal Transduction
  • Trans-Activators
  • Transcription Factors