Steering estrogen signals from the plasma membrane to the nucleus: Two sides of the coin

Abstract

Estrogen mediate its biological effects through its association with estrogen receptors (ERs). They also regulate the expression of a variety of genes involved in distinct physiological processes, including development, metabolism, and reproduction. In addition, emerging data suggest that the estrogen-estrogen receptor complex can also function as a cytoplasmic signaling molecule and may influence processes such as cardiovascular protection, bone preservation, neuroprotection, and proliferation of various cell types. Such extranuclear or nongenomic signaling pathways are rapid and supposedly independent of transcription. A recent exciting finding was that G-coupled membrane protein receptor, GPR30, an alternative to the classical ERs, is also involved in the rapid signaling of estrogen through its direct association with estrogen. These new findings combined with the recent advances in the cytoplasmic functions of proline, glutamic acid, luecine rich protein 1 (PELP1), and metastatic tumor antigen 1 short form (MTA1s) have opened a new spectrum and raised several new concerns in the field of estrogen biology and put the attention to unveil many unknown mechanistic actions of estrogen in cellular physiology. In this review, we briefly summarize what is currently known of the cellular mechanisms and physiology of estrogen's nongenomic actions in various cellular systems used by ERs.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…The cytoplasmic pool of ER allows for rapid actions of E2 via signal transduction pathways [7,59]. Palmitoylation at cysteine 447 localizes ERα to the plasma membrane and is responsible for the ligand-induced activation of MAPK and PI3K/Akt pathways in breast cancer cells [60].…”

Cross-talk between nuclear receptors and nuclear factor κB

“…Alternatively, ligand-bound ERs can regulate gene expression without directly binding to DNA through protein-protein interactions with other DNA-binding TFs in the nucleus. In addition, membrane-associated ERs mediate the non-genomic actions of estrogens, which can lead both to altered functions of proteins in the cytoplasm and to effects on the regulation of gene expression (Bjo¨rnstro¨m and Sjo¨berg, 2005;Gururaj et al, 2006;Manavathi and Kumar, 2006). The functional interaction, or cross-talk, between ER and NF-kB has been suggested to play a key role in estrogen's ability to prevent age-related conditions and tumorigenesis in vivo (Dijsselbloem et al, 2004).…”

Nutritional flavonoids impact on nuclear and extranuclear estrogen receptor activities

“…The action was not abrogated by transcriptional inhibitors and was termed 'rapid or nongenomic'. More recently evidence has started accumulating for such rapid effects being mediated by second-messenger systems that include mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), signal transducer and activator of transcription (STAT), epidermal growth factor receptor (EGFR), Src kinase, Shc kinase, protein kinase C (PKC), adenylate cyclase, GTP-binding proteins (G-proteins), and nitric oxide synthase (NOS) (Simoncini et al, 2000;Norman et al, 2004;Song et al, 2005, Levin, 2005, Manavathi and Kumar, 2005Marino et al, 2005). The number of reports on rapid E2 effects is growing tremendously indicating that the action of E2 in living cells is mediated by various pathways rather than by a single uniform mechanism.…”