Glycogen synthase kinase 3beta-mediated serine phosphorylation of the human glucocorticoid receptor redirects gene expression profiles.
Aberrant glycogen synthase kinase 3beta (GSK-3beta) activity is associated with the progression of several pathological conditions such as diabetes, Alzheimer's, and cancer. GSK-3beta regulates cellular processes by directly phosphorylating metabolic enzymes and transcription factors. Here, we discovered a new target for GSK-3beta 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-3beta. Cells expressing a GR that is incapable of GSK-3beta 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-kappaB. Furthermore, GSK-3beta-mediated GR phosphorylation inhibited glucocorticoid-dependent NF-kappaB transrepression and attenuated the glucocorticoid-dependent cell death of osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3beta and the GR pathways, resulting in altered hormone-regulated signaling. Our results also provide a mechanism by which GSK-3beta activity can dictate how cells will ultimately respond to glucocorticoids.
Molecular Endocrinology Group, 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, USA.
Amy Jo
AJ
Galliher-Beckley
Jason Grant
JG
Williams
Jennifer Brady
JB
Collins
John Anthony
JA
Cidlowski
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D012694:Serine; D003907:Dexamethasone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3