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Modulation of Glucocorticoid Receptor Phosphorylation and Transcriptional Activity by a C-Terminal-Associated Protein Phosphatase

Departments of Microbiology (Z.W., E.K., T.D., M.J.G.), Urology (M.J.G.), and Pharmacology (W.C.), New York University Cancer Institute, New York University School of Medicine, New York, New York 10016

Address all correspondence and requests for reprints to: Michael J. Garabedian, Departments of Microbiology, Urology, New York University Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, New York 10016. E-mail: garabm01{at}med.nyu.edu.

The glucocorticoid receptor (GR) is phosphorylated at three major sites on its N terminus (S203, S211, and S226), and phosphorylation modulates GR-regulatory functions in vivo. We examined the phosphorylation site interdependence, the contribution of the receptor C-terminal ligand-binding domain, and the participation of protein phosphatases in GR N-terminal phosphorylation and gene expression. We found that GR phosphorylation at S203 was greater when S226 was not phosphorylated and vice versa, indicative of intersite dependency. We also observed that a GR derivative lacking the ligand-binding domain, which no longer binds the heat shock protein 90 (Hsp90) complex, exhibits increased GR phosphorylation at all three sites as compared with the full-length receptor. A GR mutation (F602S) that produces a receptor less dependent on Hsp90 for function as well as treatment with the Hsp90 inhibitor geldanamycin also increased basal GR phosphorylation at a subset of sites. Pharmacological inhibition of serine/threonine protein phosphatases increased GR basal phosphorylation. Likewise, a reduction in protein phosphatase 5 protein levels enhanced GR phosphorylation at a subset of sites and selectively reduced the induction of endogenous GR target genes. Together, our findings suggest that GR undergoes a phosphorylation/dephosphorylation cycle that maintains steady-state receptor phosphorylation at a low basal level in the absence of ligand. Our findings also suggest that the ligand-dependent increase in GR phosphorylation results, in part, from the dissociation of a ligand-binding domain-linked protein phosphatase(s), and that changes in the intracellular concentration of protein phosphatase 5 differentially affect GR target gene expression.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Ligands:   Dexamethasone

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