Role of ERα36 in membrane-associated signaling by estrogen

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…These differential activities were subsequently understood at least in part at the molecular level based on the stabilization of distinct ER conformations (involving helix 12 of the ligand binding domain), which in turn result in differential recruiting of transcriptional coactivators and corepressors (Smith and O'Malley, 2004), in a ligand-and tissue-dependent manner (McDonnell and Wardell, 2010;Burris et al, 2013). Far less is understood regarding the mechanisms and pharmacology of rapid signaling via ERa and ERb (Banerjee et al, 2014), including their many splice variants (Kim et al, 2011;Chaudhri et al, 2014), and in particular, the agonistic rapid cellular effects of SERMs and SERDs, which can now at least be partially understood through their actions on GPER. However, just as our understanding of the actions of agonists, SERMs and SERDs for ERs has expanded over the years, GPCRs are now understood to exist in a number of activated conformations (Katritch et al, 2013), stabilized to varying extents by different ligands, that induce distinct subsets of downstream signaling pathways, processes termed functional selectivity or biased agonism (Kenakin, 2012(Kenakin, , 2013Seifert, 2013).…”

“…Values for ICI 182,780 include those for the analog ICI 164,384. ER66), splice variants have been described (Taylor et al, 2010), resulting in proteins of 46 kDa (resulting from an amino-terminal truncation due to an alternate intron-localized start site) (Kim and Bender, 2009) and 36 kDa (generated from the same start site as ER46 but with an additional truncation at the carboxy terminus) Chaudhri et al, 2014). Missing the amino terminal transcription activation domain, these proteins have been shown to act as inhibitors of ERamediated transcription and to mediate rapid signaling pathways (Wang et al, 2006).…”

Rapid steroid hormone actions via membrane receptors

“…In addition to affecting proliferation, ERα36 mediates the anti-apoptotic effect of E 2 . The mechanism involves activation of phospholipase D (PLD) at the membrane resulting in production of lysophosphatidic acid (LPA) and ultimately activation of PI3K, leading to attenuation of the caspase cascade that promotes apoptosis [64,65,76]. This mechanism of E 2 's action was found also in laryngeal cancer cells [77] and resembles the mechanism of action of androgens in prostate cancer [78] and aldosterone in vascular smooth muscle cells and kidney cells [79] (Fig.…”

“…ERα36 activates rapid signaling via PKC, ERK-MAPK, and PI3K-Akt. In addition, ERα36 plays a role in E 2 -dependent signaling via IGF-IR, EGFR, and HER2 [63] pathways, increasing proliferation and conferring antiapoptotic effects and metastatic potential in a variety of cancer cells, including those in both ER positive and negative breast tumors [17,64,76], as well as endometrial [131], laryngeal [77], colorectal [132] and lung adenocarcinoma [133].…”

The analysis of estrogen receptor-α positive breast cancer stem-like cells unveils a high expression of the serpin proteinase inhibitor PI-9: Possible regulatory mechanisms

“…In 2005 Wang et al identified and cloned a novel isoform of full-length ERα66 with a molecular weight of 36 kDa (ERα36) which is characterized by the lack of transcriptional activation domains and retains a partial ligand-binding domain (9). Although the prevalent subcellular localization of ERα36 (cytosol and cell membrane) and the lack of intrinsic transcriptional activity associate ERα36 to a non-genomic rapid estrogen signaling (10), the interplay between the diverse variants of ERs has not been fully established so far. It has been demonstrated that ERα36 can act as a dominant-negative regulator of signaling mediated by ERα66 but, on the other hand, the ERα36 expression seems to be subjected to an ERα66-dependent negative regulation (11).…”