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Modulation of Glucocorticoid Receptor Function via Phosphorylation
NAIMA ISMAILIa AND
MICHAEL J. GARABEDIANa,b
Departments of Microbiologya and Urology,b New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
Address for correspondence: Michael J. Garabedian, Depts. of Microbiology and Urology, NYU School of Medicine, 550 First Avenue, New York, NY 10016. Voice: 212-263-7662; fax: 212-263-8276. garabm01{at}med.nyu.edu
Ann. N.Y. Acad. Sci. 1024: 86-101 (2004).
The glucocorticoid receptor (GR) is phosphorylated at multiple serine residues in a hormone-dependent manner. It has been suggested that GR phosphorylation affects turnover, subcellular trafficking, or the transcriptional regulatory functions of the receptor, yet the contribution of individual GR phosphorylation sites to the modulation of GR activity remains enigmatic. This review critically evaluates the literature on GR phosphorylation and presents more recent work on the mechanism of GR phosphorylation from studies using antibodies that recognize GR only when it is phosphorylated. In addition, we present support for the notion that GR phosphorylation modifies protein-protein interactions, which can stabilize the hypophosphorylated form of the receptor in the absence of ligand, as well as facilitate transcriptional activation by the hyperphosphorylation of GR via cofactor recruitment upon ligand binding. Finally, we propose that GR phosphorylation also participates in the nongenomic activation of cytoplasmic signaling pathways evoked by GR. Thus, GR phosphorylation is a versatile mechanism for modulating and integrating multiple receptor functions.
Key Words: GR • phosphorylation • transcription • kinases
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