Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation

Post-translational modifications such as phosphorylation are known to play an important role in the gene regulation by the transcription factors including the nuclear hormone receptor superfamily of which the glucocorticoid receptor (GR) is a member. Protein phosphorylation often switches cellular a...

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Main Authors:	Kumar, Raj, Calhoun, William J
Format:	Online
Language:	English
Published:	Dove Medical Press 2008
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727889/

id	pubmed-2727889
recordtype	oai_dc
spelling	pubmed-27278892009-08-25 Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation Kumar, Raj Calhoun, William J Review Post-translational modifications such as phosphorylation are known to play an important role in the gene regulation by the transcription factors including the nuclear hormone receptor superfamily of which the glucocorticoid receptor (GR) is a member. Protein phosphorylation often switches cellular activity from one state to another. Like many other transcription factors, the GR is a phosphoprotein, and phosphorylation plays an important role in the regulation of GR activity. Cell signaling pathways that regulate phosphorylation of the GR and its associated proteins are important determinants of GR function under various physiological conditions. While the role of many phosphorylation sites in the GR is still not fully understood, the role of others is clearer. Several aspects of transcription factor function, including DNA binding affinity, interaction of transactivation domains with the transcription initiation complex, and shuttling between the cytoplasmic compartments, have all been linked to site-specific phosphorylation. All major phosphorylation sites in the human GR are located in the N-terminal domain including the major transactivation domain, AF1. Available literature clearly indicates that many of these potential phosphorylation sites are substrates for multiple kinases, suggesting the potential for a very complex regulatory network. Phosphorylated GR interacts favorably with critical coregulatory proteins and subsequently enhances transcriptional activity. In addition, the activities and specificities of coregulators may be subject to similar regulation by phosphorylation. Regulation of the GR activity due to phosphorylation appears to be site-specific and dependent upon specific cell signaling cascade. Taken together, site-specific phosphorylation and related kinase pathways play an important role in the action of the GR, and more precise mechanistic information will lead to fuller understanding of the complex nature of gene regulation by the GR- and related transcription factors. This review provides currently available information regarding the role of GR phosphorylation in its action, and highlights the possible underlying mechanisms of action. Dove Medical Press 2008-12 2008-12 /pmc/articles/PMC2727889/ /pubmed/19707462 Text en © 2008 Kumar and Calhoun, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kumar, Raj Calhoun, William J
spellingShingle	Kumar, Raj Calhoun, William J Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation
author_facet	Kumar, Raj Calhoun, William J
author_sort	Kumar, Raj
title	Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation
title_short	Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation
title_full	Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation
title_fullStr	Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation
title_full_unstemmed	Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation
title_sort	differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation
description	Post-translational modifications such as phosphorylation are known to play an important role in the gene regulation by the transcription factors including the nuclear hormone receptor superfamily of which the glucocorticoid receptor (GR) is a member. Protein phosphorylation often switches cellular activity from one state to another. Like many other transcription factors, the GR is a phosphoprotein, and phosphorylation plays an important role in the regulation of GR activity. Cell signaling pathways that regulate phosphorylation of the GR and its associated proteins are important determinants of GR function under various physiological conditions. While the role of many phosphorylation sites in the GR is still not fully understood, the role of others is clearer. Several aspects of transcription factor function, including DNA binding affinity, interaction of transactivation domains with the transcription initiation complex, and shuttling between the cytoplasmic compartments, have all been linked to site-specific phosphorylation. All major phosphorylation sites in the human GR are located in the N-terminal domain including the major transactivation domain, AF1. Available literature clearly indicates that many of these potential phosphorylation sites are substrates for multiple kinases, suggesting the potential for a very complex regulatory network. Phosphorylated GR interacts favorably with critical coregulatory proteins and subsequently enhances transcriptional activity. In addition, the activities and specificities of coregulators may be subject to similar regulation by phosphorylation. Regulation of the GR activity due to phosphorylation appears to be site-specific and dependent upon specific cell signaling cascade. Taken together, site-specific phosphorylation and related kinase pathways play an important role in the action of the GR, and more precise mechanistic information will lead to fuller understanding of the complex nature of gene regulation by the GR- and related transcription factors. This review provides currently available information regarding the role of GR phosphorylation in its action, and highlights the possible underlying mechanisms of action.
publisher	Dove Medical Press
publishDate	2008
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727889/
_version_	1611442055452557312

Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation

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