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Proline-Directed Androgen Receptor Phosphorylation.

Gao Y, Chen S - J Mol Genet Med (2013)

Bottom Line: The androgen receptor (AR) has been identified for decades and mediates essential steroid functions.This review is focused on the reported activities and significance of AR phosphorylation, with particular emphasis on proline-directed serine/threonine phosphorylation that occurs predominantly on the receptor.The marked enrichment of AR phosphorylation in the most diverse N-terminal domain suggests that targeting AR phosphorylation can be synergistic to antagonizing the C-terminal domain by clinical antiandrogens.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School 330 Brookline, MA 02115, USA.

ABSTRACT

The androgen receptor (AR) has been identified for decades and mediates essential steroid functions. Like most of biological molecules, AR functional activities are modulated by post-translational modifications. This review is focused on the reported activities and significance of AR phosphorylation, with particular emphasis on proline-directed serine/threonine phosphorylation that occurs predominantly on the receptor. The marked enrichment of AR phosphorylation in the most diverse N-terminal domain suggests that targeting AR phosphorylation can be synergistic to antagonizing the C-terminal domain by clinical antiandrogens.

No MeSH data available.


Related in: MedlinePlus

AR linear amino acid sequences of the hinge domain. Alignment of human, chimpanzee, mouse and rat AR with highlighted conserved residues (in red) and PEST sequences (underlined). Black arrow heads indicated additional phosphorylation residues (Ser646, Ser647, and Thr652) identified in the hinge region by our mass-spec studies (data not shown).
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Figure 4: AR linear amino acid sequences of the hinge domain. Alignment of human, chimpanzee, mouse and rat AR with highlighted conserved residues (in red) and PEST sequences (underlined). Black arrow heads indicated additional phosphorylation residues (Ser646, Ser647, and Thr652) identified in the hinge region by our mass-spec studies (data not shown).

Mentions: The Ser650 in the only Pro-directed serine residue that locates outside of the NTD. It resides in the hinge region and centers on the diverse PEST sequence that potentially mediates AR protein degradation (Figure 4). The hinge region contains part of the NLS (nuclear translocation signal) and regulates AR transactivation and nuclear localization, and is one major target site for modifications (acetylation, ubiquitination and methylation) [48,49]. The hinge region is also enriched in phosphorylable residues and indeed, mass-spec analysis has identified phosphorylation occurring at Ser650 and several adjacent residues (Table 1, Figure 4; data not shown). Although transient transfection assays suggested thatS650 phosphorylation has no or minimal effects on AR functional activities, study based on endogenous AR indicated that the stress kinases (JNK (c-Jun N-terminal kinase) and p38) regulate Ser 650 phosphorylation and AR nuclear export [13,17,28]. The functions of phosphorylation at the adjacent residues (Ser646, Ser647, and Thr652) are unknown (Figure 4).


Proline-Directed Androgen Receptor Phosphorylation.

Gao Y, Chen S - J Mol Genet Med (2013)

AR linear amino acid sequences of the hinge domain. Alignment of human, chimpanzee, mouse and rat AR with highlighted conserved residues (in red) and PEST sequences (underlined). Black arrow heads indicated additional phosphorylation residues (Ser646, Ser647, and Thr652) identified in the hinge region by our mass-spec studies (data not shown).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389684&req=5

Figure 4: AR linear amino acid sequences of the hinge domain. Alignment of human, chimpanzee, mouse and rat AR with highlighted conserved residues (in red) and PEST sequences (underlined). Black arrow heads indicated additional phosphorylation residues (Ser646, Ser647, and Thr652) identified in the hinge region by our mass-spec studies (data not shown).
Mentions: The Ser650 in the only Pro-directed serine residue that locates outside of the NTD. It resides in the hinge region and centers on the diverse PEST sequence that potentially mediates AR protein degradation (Figure 4). The hinge region contains part of the NLS (nuclear translocation signal) and regulates AR transactivation and nuclear localization, and is one major target site for modifications (acetylation, ubiquitination and methylation) [48,49]. The hinge region is also enriched in phosphorylable residues and indeed, mass-spec analysis has identified phosphorylation occurring at Ser650 and several adjacent residues (Table 1, Figure 4; data not shown). Although transient transfection assays suggested thatS650 phosphorylation has no or minimal effects on AR functional activities, study based on endogenous AR indicated that the stress kinases (JNK (c-Jun N-terminal kinase) and p38) regulate Ser 650 phosphorylation and AR nuclear export [13,17,28]. The functions of phosphorylation at the adjacent residues (Ser646, Ser647, and Thr652) are unknown (Figure 4).

Bottom Line: The androgen receptor (AR) has been identified for decades and mediates essential steroid functions.This review is focused on the reported activities and significance of AR phosphorylation, with particular emphasis on proline-directed serine/threonine phosphorylation that occurs predominantly on the receptor.The marked enrichment of AR phosphorylation in the most diverse N-terminal domain suggests that targeting AR phosphorylation can be synergistic to antagonizing the C-terminal domain by clinical antiandrogens.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School 330 Brookline, MA 02115, USA.

ABSTRACT

The androgen receptor (AR) has been identified for decades and mediates essential steroid functions. Like most of biological molecules, AR functional activities are modulated by post-translational modifications. This review is focused on the reported activities and significance of AR phosphorylation, with particular emphasis on proline-directed serine/threonine phosphorylation that occurs predominantly on the receptor. The marked enrichment of AR phosphorylation in the most diverse N-terminal domain suggests that targeting AR phosphorylation can be synergistic to antagonizing the C-terminal domain by clinical antiandrogens.

No MeSH data available.


Related in: MedlinePlus