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 RIS Download
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