Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/88378
Title: Lysine methylation of progesterone receptor at activation function 1 regulates both ligand-independent activity and ligand sensitivity of the receptor
Authors: Chung, Hwa Hwa
Sze, Siu Kwan
Woo, Amanda Rui En
Sun, Yang
Sim, Kae Hwan
Dong, Xue Ming
Lin, Valerie Chun-Ling
Keywords: Post-translational Modification
Protein Methylation
DRNTU::Science::Biological sciences
Issue Date: 2014
Source: Chung, H. H., Sze, S. K., Woo, A. R. E., Sun, Y., Sim, K. H., Dong, X. M., & Lin, V. C.-L. (2014). Lysine methylation of progesterone receptor at activation function 1 regulates both ligand-independent activity and ligand sensitivity of the receptor. Journal of Biological Chemistry, 289(9), 5704-5722. doi:10.1074/jbc.M113.522839
Series/Report no.: Journal of Biological Chemistry
Abstract: Progesterone receptor (PR) exists in two isoforms, PRA and PRB, and both contain activation functions AF-1 and AF-2. It is believed that AF-1 is primarily responsible for the ligand-independent activity, whereas AF-2 mediates ligand-dependent PR activation. Although more than a dozen post-translational modifications of PR have been reported, no post-translational modification on AF-1 or AF-2 has been reported. Using LC-MS/MS-based proteomic analysis, this study revealed AF-1 monomethylation at Lys-464. Mutational analysis revealed the remarkable importance of Lys-464 in regulating PR activity. Single point mutation K464Q or K464A led to ligand-independent PR gel upshift similar to the ligand-induced gel upshift. This upshift was associated with increases in both ligand-dependent and ligand-independent PR phosphorylation and PR activity due to the hyperactivation of AF-1. In contrast, mutation of Lys-464 to the bulkier phenylalanine to mimic the effect of methylation caused a drastic decrease in PR activity. Importantly, PR-K464Q also showed heightened ligand sensitivity, and this was associated with increases in its functional interaction with transcription co-regulators NCoR1 and SRC-1. These results suggest that monomethylation of PR at Lys-464 probably has a repressive effect on AF-1 activity and ligand sensitivity.
URI: https://hdl.handle.net/10356/88378
http://hdl.handle.net/10220/45806
ISSN: 0021-9258
DOI: 10.1074/jbc.M113.522839
Rights: © 2014 The American Society for Biochemistry and Molecular Biology, Inc. This paper was published in Journal of Biological Chemistry and is made available as an electronic reprint (preprint) with permission of The American Society for Biochemistry and Molecular Biology, Inc. The published version is available at: [http://dx.doi.org/10.1074/jbc.M113.522839]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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