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Ser815 Phosphorylation stabilizes the androgen receptor homodimer and stimulates ER-stress induced cell death

Kosuke Yokobori1, Masahiko Negishi1

  • 1Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.

Biochemical and Biophysical Research Communications
|December 5, 2022
PubMed

Insights

Phosphorylation of androgen receptor (AR) at Ser815 stabilizes cytoplasmic homodimers, hindering nuclear translocation and impacting prostate cell fate. This modification influences endoplasmic reticulum stress responses, potentially affecting prostate health.

Area of Science:

  • Molecular Endocrinology
  • Cell Biology
  • Prostate Cancer Research

Background:

  • The androgen receptor (AR) is crucial for prostate biology, regulating cell fate through cytoplasmic homodimerization and nuclear translocation.
  • AR phosphorylation at Ser815 is observed in mature prostates but decreases with castration or prostate cancer progression.

Purpose of the Study:

  • To investigate the functional and biological roles of androgen receptor (AR) phosphorylation at Ser815.
  • To elucidate the mechanism by which AR Ser815 phosphorylation affects AR nuclear translocation and cellular responses.

Main Methods:

  • Utilized cDNA microarray analysis in castrated mouse prostates.
  • Examined the effects of AR Ser815Asp phospho-mimetic mutant expression in PC-3 cells.

Main Results:

  • AR phosphorylation at Ser815 stabilizes cytoplasmic homodimer formation, inhibiting DHT-response nuclear translocation.
  • Castration appears to attenuate endoplasmic reticulum (ER) stress responses in mouse prostates.
  • Expression of an AR Ser815Asp phospho-mimetic mutant enhanced ER stress-induced cell death in PC-3 cells.

Conclusions:

  • Phosphorylation at AR Ser815 modulates AR function by stabilizing cytoplasmic homodimers and influencing ER stress responses.
  • AR Ser815 phosphorylation plays a role in maintaining prostate homeostasis and may be implicated in prostate cancer progression.
Keywords:
ActivationAndrogen receptorDimerizationER stressEndoplasmic reticulumPhosphorylation

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