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

Abstract

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-κB. Furthermore, GSK-3β-mediated GR phosphorylation inhibited glucocorticoid-dependent NF-κB 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.