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Mol. Cell. Biol. doi:10.1128/MCB.01672-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

EGF dependent phosphorylation and ubiquitinylation of MAGE-11 regulates its interaction with the androgen receptor

Laboratories for Reproductive Biology, Lineberger Comprehensive Cancer Center, and the Departments of Pediatrics, Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599

^* To whom correspondence should be addressed. Email: emw{at}med.unc.edu.

	Abstract

The androgen receptor (AR) is a ligand activated transcription factor that interacts with coregulatory proteins during androgen dependent gene regulation. Melanoma antigen gene protein-11 (MAGE-11) is an AR coregulator that specifically binds the AR NH₂-terminal FXXLF motif and modulates the AR NH₂- and carboxyl-terminal N/C interaction to increase AR transcriptional activity. Here we demonstrate that epidermal growth factor (EGF) signaling increases androgen dependent AR transcriptional activity through the post-translational modification of MAGE-11. EGF in the presence of dihydrotestosterone stabilizes the AR–MAGE complex through the site specific phosphorylation of MAGE-11 at Thr-360 and ubiquitinylation at Lys-240 and Lys-245. The time-dependent EGF-induced increase in AR transcriptional activity by MAGE-11 is mediated through AR activation functions 1 and 2 in association with the increased turnover of AR and MAGE-11. The results reveal a dynamic mechanism whereby growth factor signaling increases AR transcriptional activity through the covalent modification of an AR specific coregulatory protein. Sequence conservation of the MAGE-11 phosphorylation and ubiquitinylation sites throughout the MAGE gene family suggests common regulatory mechanisms for this group of cancer-testis antigens.

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