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Mol. Cell. Biol. 28 (24): 7309-7322

Copyright © 2008 by the American Society for Microbiology. All rights reserved.

Glycogen Synthase Kinase 3β-Mediated Serine Phosphorylation of the Human Glucocorticoid Receptor Redirects Gene Expression Profiles{triangledown}

Amy Jo Galliher-Beckley,1 Jason Grant Williams,2 Jennifer Brady Collins,3, and John Anthony Cidlowski1*

Molecular Endocrinology Group, Laboratory of Signal Transduction,1 Laboratory of Structural Biology,2 Microarray Center, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 277093

Received for publication 19 May 2008. Revision received 25 June 2008. Accepted for publication 25 September 2008.

Abstract: Aberrant glycogen synthase kinase 3β (GSK-3β) activity is associated with the progression of several pathological conditions such as diabetes, Alzheimer's, and cancer. GSK-3β regulates cellular processes by directly phosphorylating metabolic enzymes and transcription factors. Here, we discovered a new target for GSK-3β phosphorylation: the human glucocorticoid receptor (GR). Glucocorticoid signaling is essential for life and regulates diverse biological functions from cell growth to metabolism to apoptosis. Specifically, we found hormone-dependent GR phosphorylation on serine 404 by GSK-3β. Cells expressing a GR that is incapable of GSK-3β phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-{kappa}B. Furthermore, GSK-3β-mediated GR phosphorylation inhibited glucocorticoid-dependent NF-{kappa}B transrepression and attenuated the glucocorticoid-dependent cell death of osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3β and the GR pathways, resulting in altered hormone-regulated signaling. Our results also provide a mechanism by which GSK-3β activity can dictate how cells will ultimately respond to glucocorticoids.

* Corresponding author. Mailing address: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709. Phone: (919) 541-1564. Fax: (919) 541-1367. E-mail: cidlows1{at}niehs.nih.gov

{triangledown} Published ahead of print on 6 October 2008.

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