Extranuclear estrogen receptor's roles in physiology: lessons from mouse models

Abstract

Steroid receptors exist and function in multiple compartments of cells in most organs. Although the functions and nature of some of these receptors is being defined, important aspects of receptor localization and signaling to physiology and pathophysiology have been identified. In particular, extranuclear sex steroid receptors have been found in many normal cells and in epithelial tumors, where they enact signal transduction that impacts both nongenomic and genomic functions. Here, I focus on the progress made in understanding the roles of extranuclear estrogen receptors (ER) in physiology and pathophysiology. Extranuclear ER serve as a model to selectively intervene with novel receptor reagents to prevent or limit disease progression. Recent novel mouse models and membrane ER-selective agonists also provide a better understanding of receptor pool cross-talk that results in the overall integrative actions of sex steroids.

Keywords: membrane estrogen receptor; signal transduction; steroid receptors.

Fig. 1.

Localization of estrogen receptor (ER) at the plasma membrane. The ERα monomer is palmitolyated by DHHC7 and DHHC21 palmitoylacyltransferase (PAT) enzymes in Golgi, causing the physical asociation of ERα with caveolin-1 protein in cytoplasm. Heat shock protein 27 (Hsp27) binds to a 9-amino acid palmitoylation motif in the ligand-binding domain of ERα, probably opening the receptor structure for subsequent PAT binding and action. Upon binding of caveolin-1, caveolin-1 transports ERα to caveolae rafts (CR) in the plasma membrane. Here, caveolin-1 serves both as a structural coat protein of the caveolae and as a scaffold for ERα, linker proteins (PELP1), and numerous signaling molecules. In this confined area, membrane ERα dimerizes in response to estrogen and then activates various Gα and Gβγ proteins for selective signaling. It is not established whether endogenous ERα span the plasma membrane. In hormone-responsive breast cancer cells, membrane-initiated signaling by ERα liberates heparin-bound epidermal growth factor (HBEGF), a ligand for epidermal growth factor receptor (EGFR) family heterodimers, ultimately activating MEK/ERK, phosphatidylinositol 3-kinase (PI3K)/Akt, and other signaling cascades that affect cellular actions. Effector kinases phosphorylate proteins to alter their activity (non-genomic actions), and this signaling also conditions the chromatin environment to promote nuclear ERα actions impacting transcription (genomic actions). Nuclear-bound ERα is chaperoned by Hsp90, is not palmitoylated, and upon E₂ binding, dimerizes in the nucleus to modulate gene expression.

Fig. 2.

ERα signaling from the membrane suppresses the expression of genes involved in lipid synthesis. Estrogen-triggered signaling in liver through the ERα receptor at the membrane activates a kinase cascade, including protein kinase A/liver kinase B (LKB) signaling to AMP kinase (AMPK) activation. AMPK phosphorylates sterol regulatory element-binding protein 1 (SREBF-1), thereby preventing its NH₂-terminal cleavage by S1 or S2 proteases in Golgi. Failure of SREBF-1 processing prevents nuclear translocation of the transcription factor. Therefore, SREBF-1 is sequestered in cytoplasm and cannot augment the expression of mRNAs involved in lipid synthesis.