Phosphorylation of Steroid Hormone Receptors*

Abstract

Many observations with intact cells as well as cell-free systems suggest that receptors of the steroid hormone superfamily, along with other transcription factors, are regulated by phosphorylation. All receptors that have been analyzed carefully so far have turned out to be phosphoproteins. They are basally phosphorylated in the absence of ligand, and in many cases become hyperphosphorylated in the presence of hormone or other agonists, and sometimes of antagonists. Several studies indicate that hyperphosphorylation of receptors follows activation, and may require nuclear binding of the receptor. Serines are the predominant phosphorylated residues detected in receptors, with minor amounts of threonine. Tyrosine phosphorylation of the estrogen receptor is a subject of controversy. With various receptors, evidence has been found for phosphorylation in vivo of the N-terminal, hormone-binding, and DNA-binding domains, as well as of the hinge region. All but one of the phosphorylated sites identified in progesterone and glucocorticoid receptors by phosphopeptide mapping and sequencing are in the N-terminal domain; one is in the hinge region. Even after hormone treatment most of those sites are only partly phosphorylated, which means that several subpopulations of receptors, characterized by different states of phosphorylation and potentially different biological activities, must coexist. The majority of identified phosphorylated sites lie in consensus sequences for the PDPK. Many parallels can be discerned between phosphorylation of receptors and of other transcription factors. For example, several transcription factors become hyperphosphorylated on stimulation, and much indirect evidence points to regulation of both receptors and transcription factors by kinases and phosphatases, with cycling between different phosphorylated states. Functions of receptors that are regulated by phosphorylation are only beginning to be investigated. With transcription factors a substantial body of information is already available, and functions that appear to be thus regulated include dimerization, interactions with other proteins, binding to DNA, nuclear-cytoplasmic localization, and transcriptional activity. These and other functions may be found to be regulated by phosphorylation of receptors.

Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

“…Evidence of increased placental and pituitary expression of GR mRNA and protein after the infusion of cortisol ) suggests a similar pattern of regulation in late gestation trophoblast, in addition to fetal tissue. Previous findings of a correlation between the degree of receptor phosphorylation and functional significance provide evidence for a posttranslational mechanism of receptor processing in mediating the action of cortisol in the fetal liver (Orti et al 1992, Bamberger et al 1996.…”

Effects of Coumestrol on Estrogen Receptor Function and Uterine Growth in Ovariectomized Rats

“…The data in Figure 10 demonstrate that coumestrol pretreatment significantly shifted the dose-response curve for estradiol, and it is likely that coumestrol induction of cytosolic ER as shown in Figures 5 and 6 by causing ER activation or phosphorylation (60,61) or by enhancing ovarian release of estrogen. If this is the case, one might anticipate that the observed estrogenicity or antiestrogenicity of dietarily derived phytoestrogens such as coumestrol may be different in premenopausal and postmenopausal women.…”

“…Therefore, increasing the dose level of coumestrol fivefold (-10 mg/kg body weight) failed to alter the response profiles at these short times (1-3 days) after injection. Whether this increase in cytosolic ER concentration after coumestrol treatment reflects phytoestrogeninduced ER activation, ER phosphorylation, and/or the stimulation of ER gene transcription remains to be resolved (61,62).…”

The role of estrogens and estrogen receptor signaling pathways in cancer and infertility: the case of schistosomes

“…The hormone-binding domain (HBD), located at the ER C terminus, exhibits two regions of sequence homology with other hormone receptors. These regions confer hormone specificity and selectivity to ER [22][23][24][25][26].…”