Steroid hormone receptors and their regulation by phosphorylation

The steroid/thyroid hormone receptor superfamily of ligand-activated transcription factors encompasses not only the receptors for steroids, thyroid hormone, retinoids and vitamin D, but also a large number of proteins whose functions and/or ligands are unknown and which are thus termed orphan receptors. Recent studies have highlighted the importance of phosphorylation in receptor function. Although most of the phosphorylation sites are serine and threonine residues, a few of the family members are also phosphorylated on tyrosine. Those steroid receptor family members that are bound to heat-shock proteins in the absence of ligand typically are basally phosphorylated and exhibit increases in phosphorylation upon ligand binding. Most of these sites contain Ser-Pro motifs, and there is evidence that cyclin-dependent kinases and MAP kinases (mitogen-activated protein kinases) phosphorylate subsets of these sites. In contrast, phosphorylation sites identified thus far in members of the family that bind to DNA in the absence of hormone typically do not contain Ser-Pro motifs and are frequently casein kinase II or protein kinase A sites. Phosphorylation has been implicated in DNA binding, transcriptional activation and stability of the receptors. The finding that some of the steroid receptor family members can be activated in the absence of ligand by growth factors or neurotransmitters that modulate kinase and/or phosphatase pathways underscores the role of phosphorylation in receptor function. Hence this family of transcription factors integrates signals from ligands as well as from signal transduction pathways, resulting in alterations in mRNA and protein expression that are unique to the complex signals received.