GLUCOCORTICOID RECEPTOR PHOSPHORYLATION - OVERVIEW, FUNCTION AND CELLCYCLE-DEPENDENCE

All steroid hormone receptors are phosphorylated and undergo hormone-i nduced hyperphosphorylation. Most phosphorylated residues identified s o far are serines in the N-terminal domain. Other residues and domains may also be phosphorylated, e.g. the estrogen receptor is phosphoryla ted on tyrosine in the hormone-binding domain. Many sites lie in conse nsus sequences for proline-directed, cell cycle-associated kinases. In some receptors hyperphosphorylation is induced by hormone antagonists as well as agonists, and leads to new phosphorylated sites. With gluc ocorticoid receptors, hyperphosphorylation is specific for glucocortic oid agonists, follows receptor activation and produces no new sites. R ate studies suggest that hyperphosphorylation is due to accelerated ph osphorylation rather than delayed dephosphorylation. Evidence to date indicates that steroid hormone receptor phosphorylation serves not as an on-off switch but modulates function more subtly. Mutations of phos phorylated sites to alanine have been found to decrease activity by 0 to 90%, depending on mutated site, cell type, reporter gene and hormon e concentration. With glucocorticoid receptors, some alanine mutants a re up to 75% less active in hormone-induced transactivation of certain reporter genes. They are also inactive in hormone-induced repression of transcription of their own gene and down regulation of the receptor protein. Furthermore, they are much less sensitive to degradation. Bo th basal phosphorylation and hormone-dependent hyperphosphorylation of these receptors are cell cycle-dependent, basal phosphorylation being low in S phase and high in G2/M and hyperphosphorylation the reverse, suggesting a causal relation to the cell cycle-dependence of glucocor ticoid activity reported with several cell lines. Hyperphosphorylation appears to be regulated by basal phosphorylation through negative cha rge in the N-terminal domain, which in S phase is relatively low and p ermits hyperphosphorylation, but in G2/M is relatively high and blocks hyperphosphorylation. (C) 1998 Elsevier Science Ltd. All rights reser ved.