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Phosphorylation of nuclear receptors: Novelty and therapeutic implications

Sawako Shindo1, Satoru Kakizaki2, Toshiyuki Sakaki3

  • 1Department of Environmental Toxicology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.

Pharmacology & Therapeutics
|June 17, 2023
PubMed

Insights

Nuclear receptors (NRs) regulate biological functions. Phosphorylation, a key modification, influences NR activity in vivo, particularly for estrogen and androgen receptors, presenting a potential drug target.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Biochemistry

Background:

  • Nuclear receptors (NRs) are crucial regulators of diverse biological functions across multiple organs.
  • While ligand binding is a primary activation mechanism for NRs, phosphorylation also plays a significant role.
  • The in vivo biological relevance of NR phosphorylation has been historically under-established despite research on specific residue modifications.

Purpose of the Study:

  • To review the current understanding of nuclear receptor phosphorylation.
  • To highlight the physiological relevance of phosphorylation in NR function, particularly in conserved motifs.
  • To focus on estrogen receptors (ERs) and androgen receptors (ARs) as key examples and explore phosphorylation as a therapeutic target.

Main Methods:

  • Literature review of recent studies on NR phosphorylation.
  • Analysis of research focusing on conserved phosphorylation motifs within DNA- and ligand-binding domains.
  • Examination of studies investigating the in vivo roles of NR phosphorylation.

Main Results:

  • Recent studies confirm the physiological relevance of NR phosphorylation, especially within conserved motifs.
  • Phosphorylation sites in DNA- and ligand-binding domains are critical for NR function.
  • Estrogen and androgen receptors serve as prominent examples illustrating the impact of phosphorylation.

Conclusions:

  • NR phosphorylation is a critical regulatory mechanism with established physiological relevance.
  • Targeting NR phosphorylation offers a promising therapeutic strategy, particularly for ER and AR related conditions.
  • Further research into NR phosphorylation can unlock new avenues for drug development.
Keywords:
DNA-binding domainLigand-binding domainNuclear receptorPhosphorylationTranscription

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