Phosphorylation: a fundamental regulator of steroid receptor action

Abstract

Steroid hormone receptors (SHRs) are hormone-activated transcription factors involved in numerous cellular functions and in health and disease. Their activities depend on the cellular level of the receptor, the presence of coregulator proteins, and the cell signaling pathways that are active in the cell. SHRs and their coregulators are phosphorylated on multiple sites by a wide variety of kinases. Each site may contribute to multiple functions and the net effect of an individual phosphorylation depends on the activating kinase. Here we discuss functions of known SHR phosphorylation sites, kinase regulation, evidence of translational relevance, and crosstalk between SHRs and cell signaling pathways. Understanding how cell signaling pathways regulate SHRs might yield novel therapeutic targets for multiple human diseases.

Keywords: cell signaling; coactivator; phosphorylation; steroid receptor.

Figure 1. Mechanisms of steroid hormone receptor (SHR) action

In the absence of ligand, SHRs are bound to heat shock protein (HSP) complexes. Upon binding of ligand and/or activation of cell signaling pathways, SHRs dissociate from these complexes, form homodimers, translocate to the nucleus, and bind to SHR response elements. Following this binding, coactivator complexes (CoA) are recruited, facilitating transcription of target genes. Alternatively, SHRs can bind to other transcription factors (TF) sitting on TF response elements, resulting in the recruitment of CoAs and induction of target gene expression. SHRs can also inhibit gene transcription. Finally, SHRs also interact with and activate kinases, such as protein kinase B/Akt (AKT) and c-Src (SRC) resulting in phosphorylation and activation of other TFs bound to TF response elements and altered target gene transcription.

Figure 2. Structure and phosphorylation sites of SHRs

The numbers indicate the amino acids that mark the domain boundaries in the individual receptors between the NTD, DBD=, hinge region (H), and LBD. Solid lines indicate sites that have been determined using radiolabeling, protein sequencing, or mass spectrometry analysis of sites in purified proteins; dotted lines indicate sites identified by phosphoproteomic approaches, and dashed lines indicate sites identified by in vitro phosphorylation or by homology with sites in rodents. References for identification of the sites, with the exception of the MR sites Ser128, Thr159, and Ser250 [80] can be found at www.phosphosite.org. Note that the proposed Ser/Thr sites reported on www.phosphosite.org that have not been detected by at least one of these direct methods are not included in the figure. AR, androgen receptor; ER, estrogen receptor; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PR, progesterone receptor. S, serine; T, threonine.