Posttranslational Modification of the Androgen Receptor in Prostate Cancer
<p>The androgen receptor (AR) contains three major functional domains and several activation functional units that control its activity. The AR protein is comprised of a large NH<sub>2</sub>-terminal domain (NTD), which harbors the transcriptional activation function-1 (AF1), containing the transcriptional activation unit 1 (TAU1) and TAU5. Within the TAU1 and TAU5 regions two core motifs, LKDIL and WHTLF, have been identified to regulate androgen-dependent and androgen-independent AR activity respectively [<a href="#b12-ijms-14-14833" class="html-bibr">12</a>,<a href="#b19-ijms-14-14833" class="html-bibr">19</a>–<a href="#b22-ijms-14-14833" class="html-bibr">22</a>]. Other domains include the DNA binding domain (DBD) that contains two zinc fingers (Z), a short flexible hinge region (H), and the <span class="html-italic">C</span>-terminal domain (CDT) that contains the ligand binding domain (LBD) and the transcriptional activation function-2 (AF2).</p> ">
<p>Androgen receptor and its truncated splice variants share structural similarity in the NTD and DBD. Exon skipping or splicing of cryptic exons (CE) yield <span class="html-italic">C</span>-terminal truncated AR splice variants (AR-Vs). The splice variants lack the LBD and are constitutively active in the absence of ligand. Increased expression of AR-Vs has been identified in castration-resistant prostate cancer (CRPC).</p> ">
<p>The AR is a phosphoprotein with several serine, threonine, and tyrosine residues that are phosphorylated. The NTD contains most of the phosphorylated residues that regulate AR cellular localization, stability and its transcriptional activity.</p> ">
<p>AR transcriptional activity and protein stability are regulated by additional posttranslational modifications to the AR protein. SUMOylation (SUMO) occurs in the NTD, while methylation (Me) and acetylation (Ac) modifies the hinge region and ubiquitination (Ub) takes place in the LBD. These modifications alter transcriptional activity and protein stability.</p> ">
Abstract
:1. Introduction
2. Phosphorylation of the AR
2.1. Serine and Threonine Phosphorylation of the AR
2.2. Tyrosine Phosphorylation of the AR
2.3. Phosphatases That Affect the AR
3. Acetylation of the AR
4. Methylation of the AR
5. Ubiquitination of the AR
6. SUMOylation of the AR
7. Conclusions
Acknowledgments
Conflict of Interest
References
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Residue | Kinase/phosphatase | Function | References |
---|---|---|---|
S81 | CDK1, CDK5, CDK9 | Localization protein stability | [59] |
PP2 | Cell growth transcription | [60] | |
S94 | PP2 | Transcription | [60] |
S213 | PI3K/AKT1 | Localization | [61–63] |
PIM-1 | Stability | [59,64] | |
Y267 | Ack | Cell growth transcription | [65–68] |
Src | |||
T280/S291 | AurA | Cell growth transcription | [69] |
S308 | PP2 | Transcription | [60] |
Y363 | Ack | Cell growth transcription | [66] |
S424 | PP2 | Transcription stability | [60] |
PP1 | |||
S515 | MAPK | Transcription degradation | [70,71] |
CDK7 | |||
Y534 | Src | Localization cell cycle transcription | [68,72] |
S578 | Localization transcription | [71] | |
S650 | ERK1/JNK1/p38-alpha | Localization | [73] |
Transcription | [74] | ||
PP1 | Localization | [75] | |
S791 | PI3K/AKT1 | Transcription apoptosis localization | [61–63] |
T850 | PIM-1L | Stability | [76] |
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Van der Steen, T.; Tindall, D.J.; Huang, H. Posttranslational Modification of the Androgen Receptor in Prostate Cancer. Int. J. Mol. Sci. 2013, 14, 14833-14859. https://doi.org/10.3390/ijms140714833
Van der Steen T, Tindall DJ, Huang H. Posttranslational Modification of the Androgen Receptor in Prostate Cancer. International Journal of Molecular Sciences. 2013; 14(7):14833-14859. https://doi.org/10.3390/ijms140714833
Chicago/Turabian StyleVan der Steen, Travis, Donald J. Tindall, and Haojie Huang. 2013. "Posttranslational Modification of the Androgen Receptor in Prostate Cancer" International Journal of Molecular Sciences 14, no. 7: 14833-14859. https://doi.org/10.3390/ijms140714833