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.
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
Mol. Cell
Date: Sep. 24, 2004
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