br Membrane receptor Indirect non genomic
Membrane receptor: Indirect non-genomic signaling As mentioned above, not all Fmoc-Gln(Trt)-OH responses fit the classical genomic model of steroid action. The observation of excessively fast estrogen-induced biological responses led to the development of the hypothesis that estrogen could be acting by mechanisms not involving direct target gene transcription and protein synthesis, and the subsequent discovery of the GPER1 (Prossnitz & Barton, 2011). Non-genomic actions of estrogen often involve activation of signal-transduction mechanisms with the subsequent production of intracellular second messengers, cAMP regulation and protein-kinase activation of signaling cascades that result in indirect changes in gene expression (Lösel & Wehling, 2003) (Fig. 7). The protein-kinase cascades can be classified into four major ones: (1) the phospholipase C (PLC)/protein kinase C (PKCs) pathway (Marino, Pallottini, & Trentalance, 1998), (2) the Ras/Raf/MAPK cascade (Dos Santos et al., 2002; Watters, Campbell, Cunningham, Krebs, & Dorsa, 1997), (3) the phosphatidyl inositol 3 kinase (PI3K)/Akt kinase cascade (Marino, Acconcia, & Trentalance, 2003), and (4) the cAMP/protein kinase A (PKA) signaling pathway (Gu & Moss, 1996; Picotto, Massheimer, & Boland, 1996). Additionally, GPER1 binding to estrogens promotes estrogen-dependent activation of adenylyl cyclase and epidermal growth factor receptor (EGFR). Subsequent phosphorylation of transcription factors by the protein kinases mentioned above can alter their function and ability to bind to genomic sequences to affect gene expression. Examples of transcription factors that are affected by these signaling mechanisms include: Elk-1, CREB, CCAAT-enhancer-binding protein beta (C/EBPβ), the NF-κB complex, and the signal transducer and activator of transcription (STAT) family (Cavalcanti, Lucas, Lazari, & Porto, 2015; Fox, Andrade, & Shupnik, 2009; Furth, 2014; Kousteni et al., 2003; Laliotis et al., 2013; Ozes et al., 1999; Romashkova & Makarov, 1999). Thus, by activating these non-genomic to genomic mechanisms, the estrogen receptors ERα and ERβ indirectly regulate gene transcription at alternative DNA response elements, in addition to the abovementioned genomic effects involving direct binding to EREs (Fig. 7). Another interesting fact is that both ERα and ERβ are also targets for phosphorylation by protein kinases including MAPKs, indicating that non-genomic actions of estrogens may also involve self-regulation of receptor expression (de Leeuw, Neefjes, & Michalides, 2011; Kato et al., 1995). Both the membrane bound estrogen receptor GPER1, and some variants of the ERα and ERβ have been associated to non-genomic estrogen signaling (Barton et al., 2018; Filardo & Thomas, 2012). It has been suggested that non-genomic actions of the ERα and ERβ could be mediated through a sub-population of receptors that located at the cell membrane and can activate intracellular signaling cascades (Razandi, Pedram, Merchenthaler, Greene, & Levin, 2004). At the cell membrane, the ERα and ERβ can interact with scaffold proteins such as caveolin-1 and MNAR/PELP-1 (modulator of non-genomic activity of estrogen receptor) (Chambliss et al., 2000; Cheskis et al., 2008; Shaul & Anderson, 1998). By proximity, the ERα and ERβ also interact with G proteins, various membrane receptors (e.g., tyrosine kinase, insulin growth factor 1, and epidermal growth factor receptors), and signaling molecules including ras, Src and PI3 kinases, ErbB2 (HER-2/neu) and Shc that are located at or near the membrane (Boonyaratanakornkit, 2011; Li et al., 2007; Migliaccio et al., 1996; Song et al., 2010; Song, Zhang, Chen, Bao, & Santen, 2007; Song, Zhang, & Santen, 2005). Interactions with these molecules promotes intracellular activation of mitogen activated protein kinases (MAPK) and protein kinase B (Akt) signaling pathways that can affect transcriptional regulation (Li et al., 2010). While there is no clear consensus among the experts in the field about binding of ERα and ERβ to the plasma membrane, it appears that the mechanisms described above are cell-type specific and activated under certain physiological events, and by specific receptor variants (Li, Haynes, & Bender, 2003).