Steroid receptor phosphorylation: Assigning function to site-specific phosphorylation

Abstract

Steroid receptors (SRs) are hormone-activated transcription factors important for a wide variety of cellular functions. Post-translational modifications of SRs, including phosphorylation, ubiquitination, acetylation, and sumoylation regulate their expression and function. The remarkable number of phosphorylation sites in these receptors and the wide variety of kinases shown to modulate phosphorylation influence the integration between cell-signaling pathways and SR action. These phosphorylation sites have been identified in all of the functional domains with the majority being located within the amino-terminal portions of the receptors. The regulation of function is receptor specific, site specific, and often dependent on the cellular context. Numerous roles for site-specific phosphorylation have been elucidated including sensitivity of hormone response, DNA binding, expression, stability, subcellular localization, dimerization, and protein-protein interactions that can determine the regulation of specific target genes. This review summarizes the current knowledge regarding receptor site-specific phosphorylation and regulation of function. As functional assays become more sophisticated, it is likely that additional roles for phosphorylation in receptor function will be identified.

Figure 1. Steroid receptor action

In the absence of hormone, steroid receptor (SR) monomers are associated with chaperone complexes that include heat shock protein 90 (hsp90), p23, and cochaperones containing tetratricopeptide repeats (TPR). Hormone binding activates SRs by inducing conformational changes, dissociation of the chaperone complex, nuclear translocation, dimerization, binding to hormone response elements (HRE), and recruitment of a series of coactivators (CoA) to regulate target gene transcription. SRs can bind directly to HREs or indirectly by interacting with other transcription factors (TF) by tethering. Site-specific phosphorylation (P) of receptors increases subsequent to hormone binding, with some increases occurring rapidly, and others with delayed kinetics. In some cases, upon hormone binding, receptors will interact with Src tyrosine kinase (Src) outside the nucleus, thus activating Src and downstream kinases including p42/p44 MAPK. Alternatively, rapid signaling through growth factors (GF) and associated growth factor receptors (GFR) can activate kinase pathways that can enhance phosphorylation of SRs and converge upon and activate target genes.

Figure 2. Domain structures and phosphorylation site locations of human steroid receptors

The numbers of the amino acids found at the boundaries in the individual receptors between the NTD (amino-terminal domain), DBD (DNA binding domain), H (hinge region), and LBD (ligand binding domain) are indicated. Phosphorylation sites are indicated by the arrowheads. PR, progesterone receptor; ER, estrogen receptor; AR, androgen receptor; GR, glucocorticoid receptor; S, serine; T, threonine; Y, tyrosine. A summary of the locations of phosphorylation sites can be found at Phosphosite (http://www.phosphosite.org) (79).