Elsevier

Cellular Signalling

Volume 15, Issue 4, April 2003, Pages 355-366
Cellular Signalling

Review article
Nuclear receptors: integration of multiple signalling pathways through phosphorylation

https://doi.org/10.1016/S0898-6568(02)00115-8Get rights and content

Abstract

Nuclear receptors (NRs) orchestrate the transcription of specific gene networks in response to binding of their cognate ligand. They also act as mediators in a variety of signalling pathways through integrating diverse phosphorylation events. NR phosphorylation concerns all three major domains, the N-terminal activation function (AF-1), the ligand-binding and the DNA binding domains. Often, phosphorylation of NRs by kinases that are associated with general transcription factors (e.g. cdk7 within TFIIH), or activated in response to a variety of signals (MAPKs, Akt, PKA, PKC), facilitates the recruitment of coactivators or of components of the transcription machinery and, therefore, cooperates with the ligand to enhance transcription activation. But phosphorylation can also contribute to the termination of the ligand response through inducing DNA dissociation or NR degradation or through decreasing ligand affinity. These different modes of regulation reveal an unexpected complexity of the dynamics of NR-mediated transcription. In addition, deregulation of NR phosphorylation may impact their action in certain diseases or cancers.

Introduction

Steroid and thyroid hormones, as well as certain vitamins and lipid metabolites, play a critical role in the development and homeostasis of vertebrate tissues through their regulatory effects on cell differentiation, proliferation, survival and apoptosis. They regulate the expression of specific subsets of genes within target tissues through binding nuclear receptors (NRs), which function as ligand-dependent transcription factors. The receptors for steroid hormones include the oestrogen receptor (ER), the androgen receptor (AR), the progesterone receptor (PR) and the glucocorticoid receptor (GR). ER, PR and AR are predominantly growth stimulatory receptors in their major target organs such as breast and prostate, while GR is mainly antiproliferative [1]. Certain steroid nuclear receptors (e.g. AR and GR) are held in the cytoplasm, in association with chaperone complexes (Fig. 1). Ligand binding acts as a switch-on, releasing them from the chaperone molecules. Then NRs dimerize, enter the nucleus and bind to response elements within the regulatory regions of target genes [2], [3].

The receptors for nonsteroidal ligands such as the vitamin D receptor (VDR), the retinoic acid receptors (RARs), the retinoid X receptors (RXRs) and the peroxisome proliferator activated receptors (PPARs) have a pronounced antiproliferative potential in certain cellular systems, which is linked to their capacity to induce differentiation [1], [4]. In contrast to the steroid receptors, these NRs are found primarily in the nucleus (Fig. 1). In the absence of ligand, they are associated with histone deacetylase-containing complexes tethered through corepressors. This process results in chromatin compaction and silencing of the promoter regions of the receptors' target genes. Upon agonist binding, the corepressor-binding interface is destabilized, leading to their dissociation.

Liganded NRs (either steroid or nonsteroid receptors), bound to their response elements, are targeted by coregulatory complexes (Fig. 1) including chromatin remodellers and modifiers, which decompact repressive chromatin. These events facilitate the recruitment of the transcription machinery (the General Transcription Factors and RNA Polymerase II) in a coordinated and/or combinatorial manner [5], [6], leading to transcription initiation. Then, like most transcription factors, most NRs are degraded by the ubiquitin–proteasome pathway (for review see Ref. [7]). Cotranscriptionally, NRs can integrate the signalling of other pathways, as they are targets for sequential and/or coordinated phosphorylation events. These events can occur in the absence of the natural ligand, leading to apparently ligand-independent activities. This review will focus on (i) at which residues NRs are phosphorylated, (ii) by which kinases and (iii) how phosphorylation events regulate NR activation and deactivation.

Section snippets

The basics of nuclear receptors' structure and function

Nuclear hormone receptors exhibit a conserved modular structure with six regions (A–F) (Fig. 2). The determination of the crystal structures of NR domains [8], [9], [10], [11], [12], [13], [14], [15] clarified the diverse mechanisms involved in ligand-dependent receptor activation [16], [17]. The C-terminal E region which encompasses the ligand-binding domain (LBD) is well conserved among NRs. It contains 12 alpha-helices (H1 to H12) with a dimerization interface formed mainly by helices H9 and

Nuclear hormone receptors are phosphorylated mainly in their AF-1, AF-2 and DNA binding domains

The majority of the NR-phosphorylated residues lie within the N-terminal A/B region as shown in Fig. 2 and Table 1. For certain NRs such as PR, phosphorylation of this region is rather complex with at least 13 phosphorylation sites. For others such as RARs or PPARs, phosphorylation of this region concerns only one or two residues. Note that VDR is an exception, as this region is not phosphorylated, probably due to its very short length. Most of the sites located in the N-terminal A/B region of

Positive regulation of NR-mediated transcription through phosphorylation in response to multiple signals

NRs are also substrates for a multitude of kinases activated by a variety of signals, independently of the ligand (Fig. 2 and Table 1). For most NRs (ERα, ERβ, PPARα and AR), phosphorylation of the N-terminal A/B region by MAPKs (Erks, p38MAPK, JNKs) or Akt helps the recruitment of coactivators [55], [56], [57], [88], [89], [90], thereby facilitating the recruitment of chromatin remodellers and modifiers, which decompact repressive chromatin (Fig. 4). Finally, it increases the efficiency of

NR phosphorylation and inhibition of their transcriptional activity

Phosphorylation events can also inactivate NRs, probably to switch off their activity (Fig. 5). Inhibition of transcriptional activity has been observed subsequently to the phosphorylation of NRs in their DBD. Phosphorylation of residues involved in the recognition of the cognate response elements induces NR dissociation from the promoter, therefore promoting their escape from the transcription initiation complex (Fig. 5). This has been described for VDR upon phosphorylation by PKC [76].

Nuclear receptor phosphorylation in cancers

Several lines of evidence indicate that NR phosphorylation plays a crucial role in the development of certain cancers such as breast, ovarian and prostate cancers. In most of these tumours, the MAPK and Akt kinase pathways exert increased activity, due to amplification of receptor protein–tyrosine kinases (RPTKs) [117] such as HER-2/neu [118], [119] or deregulated activity of cytoplasmic protein–tyrosine kinases (c-Src, c-Abl or bcr-Abl). This has been correlated with a ligand-independent

Conclusion and perspectives

Ligand-dependent gene-specific transcription is orchestrated by nuclear receptors, which, upon ligand binding, become activated and trigger a cascade of events resulting in an appropriately remodelled chromatin template with a functional preinitiation complex positioned for transcription. The present review demonstrates that the activity of nuclear receptors can be finely tuned through integration of diverse phosphorylation events (see Fig. 6). Generally, phosphorylation by kinases associated

Acknowledgements

I am particularly grateful to Hinrich Gronemeyer for the critical reading of this review. I acknowledge Dr. J. Conaway and Dr. R. Conaway for helpful discussions. Many thanks also to Julie Bastien, Anne Tarrade and Emilie Gaillard for enthusiastic discussions and criticism. I also thank all the past and present members of the group for their contribution to the work. I am also very grateful to Prof. P. Chambon for constant support. Our studies mentioned in the text have been supported by funds

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