Minireview: Extranuclear steroid receptors: roles in modulation of cell functions

Abstract

Steroid receptors existing outside the nucleus are increasingly being recognized in many organs and cell types, impacting the biology of bone, the heart and blood vessels, and the central nervous system. Some controversy exists as to the nature of the receptors at the plasma membrane. However, compelling evidence has been advanced that at least some classical steroid receptors mediate steroid ligand actions originating as signaling from the cell surface. Here I review the recent findings in this evolving field emphasizing the in vivo impact of these receptor pools with a focus on estrogen receptors.

Fig. 1.

Model of ERα trafficking and signaling from the PM. In the Golgi, monomeric ERα is bound at cysteine 447 by Hsp27, promoting palmitoylation by an unknown palmitoylacyltransferase (PAT). I speculate Hsp27 opens up the ligand-binding domain structure to allow access by the PAT. Palmitoylation promotes monomeric ERα association with caveolin-1, the protein that transports ERα to caveolae rafts (CR) in the PM. ERα has been found within isolated CR but might adopt a tethering conformation to caveolin-1/CR in vivo. Caveolin-1 serves as a protein scaffold along with MNAR (modulator of nongenomic action of the estrogen receptor)/Pelp-1 to bring together components of the signalsome. ERα physically associates with and activates various Gα and Gβγ subunits depending upon estrogen binding that promotes receptor dimerization. G protein stimulation leads to multiple early signals including proximal kinase activation (e.g. Src) and cross talk to growth factor receptor tyrosine kinases (e.g. EGF receptor) in breast cancer cells. The growth factor receptor ultimately signals through multiple pathways to cell functions. Transport of ERα to the nucleus originates from the endoplasmic reticulum perhaps via the Golgi, chaperoned by Hsp90. Components of trafficking to the PM have been comparably established for classical PRs and ARs. HBEGF, Heparin-bound epidermal growth-factor.