MCB Accepts, published online ahead of print on 23 July 2007

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Mol. Cell. Biol. doi:10.1128/MCB.01695-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Regulation of SRC-3 intercompartmental dynamics by ER and phosphorylation

Larbi Amazit, Luigi Pasini, Adam T. Szafran, Valeria Berno, Ray-Chang Wu, Mielke Marylin, Elizabeth D. Jones, Maureen G. Mancini, Cruz A. Hinojos, Bert W. O'Malley, and Michael A. Mancini^*

^* To whom correspondence should be addressed. Email: mancini{at}bcm.edu.

Steroid Receptor Coactivator-3 (SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM1) is a p160 family transcription coactivator and a known oncogene. Despite its importance, the functional regulation of SRC-3 remains poorly understood within a cellular context. Using a novel combination of live cell, high throughput, and fluorescent microscopy, we report SRC-3 to be a nucleocytoplasmic shuttling protein whose intracellular mobility, solubility, and cellular localization is regulated by phosphorylation and estrogen receptor- (ER) interactions. We show that both chemical inhibition and siRNA reduction of the MAP/ERK1/2 kinase (MEK1/2) pathway induces a cytoplasmic shift in SRC-3 localization, whereas stimulation by EGF signaling enhances its nuclear localization by inducing phosphorylation at T24, S857, and S860, known participants in the phosphocode that regulates SRC-3 activity. Accordingly, the cytoplasmic localization of a non-phosphorylatable SRC-3 mutant further supported these results. In the presence of ER, U0126 also dramatically reduces: 1) ligand-dependent colocalization of SRC-3 and ER; 2) formation of ER-SRC-3 complexes in cell lysates; and 3) SRC-3 targeting to a visible, ER-occupied and -regulated prolactin promoter array. Taken together, these results indicate that phosphorylation coordinates SRC-3 coactivator function by linking the probabilistic formation of transient nuclear receptor-coactivator complexes with its molecular dynamics and cellular compartmentalization. Technically and conceptually, these findings have a new and broad impact upon evaluating mechanisms of action of gene regulators at a cellular systems level.

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