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Glucocorticoid receptor phosphorylation: overview, function and cell cycle-dependence
J E Bodwell1, J C Webster, C M Jewell
1Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756, USA.
The Journal of Steroid Biochemistry and Molecular Biology
|August 12, 1998
Summary
Steroid hormone receptor phosphorylation, particularly hyperphosphorylation, subtly modulates receptor function rather than acting as an on-off switch. This process is cell cycle-dependent, impacting receptor activity and stability.
Area of Science:
- Molecular Biology
- Cell Biology
- Endocrinology
Background:
- Steroid hormone receptors are known to be phosphorylated, with hormone-induced hyperphosphorylation occurring in most cases.
- Phosphorylation sites are predominantly serines in the N-terminal domain, but other residues and domains can also be modified.
Purpose of the Study:
- To investigate the role and regulation of steroid hormone receptor phosphorylation, focusing on hormone-induced hyperphosphorylation.
- To explore the functional consequences of altered phosphorylation, including its relationship with the cell cycle.
Main Methods:
- Analysis of phosphorylated residues and domains in various steroid hormone receptors.
- Site-directed mutagenesis (e.g., alanine substitutions) to assess the impact of phosphorylation.
- Cell cycle analysis to correlate phosphorylation patterns with receptor activity.
Main Results:
- Hyperphosphorylation is not a simple on-off switch but a modulator of receptor function, with mutations decreasing activity by up to 90%.
- Glucocorticoid receptor hyperphosphorylation is specific to agonists, follows activation, and does not create new sites, unlike some other receptors.
- Both basal and hormone-dependent phosphorylation are cell cycle-dependent, influencing glucocorticoid receptor activity, repression, and protein stability.
Conclusions:
- Steroid hormone receptor phosphorylation plays a subtle, modulatory role in receptor function, influenced by agonists, antagonists, and the cell cycle.
- The N-terminal domain's negative charge, regulated by basal phosphorylation, controls hyperphosphorylation and is linked to cell cycle-dependent glucocorticoid activity.