Extra-nuclear estrogen signaling

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Homo sapiens
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In addition to its well-characterized role in estrogen-dependent transcription, estrogen (beta-estradiol, also known as E2) also plays a rapid, non-genomic role through interaction with receptors localized at the plasma membrane by virtue of dynamic palmitoylation. Estrogen receptor palmitoylation is a prerequisite for the E2-dependent activation of extra-nuclear signaling both in vitro and in animal models (Acconcia et al, 2004; Acconcia et al, 2005; Marino et al, 2006; Marino and Ascenzi, 2006). Non-genomic signaling through the estrogen receptor ESR1 also depends on receptor arginine methylation by PMRT1 (Pedram et al, 2007; Pedram et al, 2012; Le Romancer et al, 2008; reviewed in Arnal, 2017; Le Romancer et al, 2011 ).
E2-evoked extra-nuclear signaling is independent of the transcriptional activity of estrogen receptors and occurs within seconds to minutes following E2 administration to target cells. Extra-nuclear signaling consists of the activation of a plethora of signaling pathways including the RAF/MAP kinase cascade and the PI3K/AKT signaling cascade and governs processes such as apoptosis, cellular proliferation and metastasis (reviewed in Hammes et al, 2007; Handa et al, 2012; Lange et al, 2007; Losel et al, 2003; Arnal et al, 2017; Le Romancer et al, 2011). ESR-mediated signaling also cross-talks with receptor tyrosine kinase, NF- kappa beta and GPCR signaling pathways by modulating the post-translational modification of enzymes and other proteins and regulating second messengers (reviewed in Arnal et al, 2017; Schwartz et al, 2016; Boonyaratanakornkit, 2011; Biswas et al, 2005). In the nervous system, E2 affects neural functions such as cognition, behaviour, stress responses and reproduction in part by inducing such rapid extra-nuclear responses (Farach-Carson and Davis, 2003; Losel et al, 2003), while in endothelial cells, non-genomic ESR-dependent signaling also regulates vasodilation through the eNOS pathway (reviewed in Levin, 2011).
Extra-nuclear signaling additionally cross-talks with nuclear estrogen receptor signaling and is required to control ER protein stability (La Rosa et al, 2012)
Recent data have demonstrated that the membrane ESR1 can interact with various endocytic proteins to traffic and signal within the cytoplasm. This receptor intracellular trafficking appears to be dependent on the phyical interaction of ESR1 with specific trans-membrane receptors such as IGR-1R and beta 1-integrin (Sampayo et al, 2018)
Literature References
PubMed ID Title Journal Year
21680538 Cracking the estrogen receptor's posttranslational code in breast tumors

Poulard, C, Corbo, L, Renoir, JM, Sentis, S, Cohen, P, Le Romancer, M

Endocr. Rev. 2011
27288742 Rapid steroid hormone actions via membrane receptors

Verma, A, Schwartz, Z, Bivens, CB, Schwartz, N, Boyan, BD

Biochim. Biophys. Acta 2016
15496458 Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol

Marino, M, Bocedi, A, Trentalance, A, Ascenzi, P, Acconcia, F, Visca, P, Tomasi, V, Spisni, E

Mol. Biol. Cell 2005
22446104 Palmitoylation regulates 17β-estradiol-induced estrogen receptor-α degradation and transcriptional activity

Marino, M, Acconcia, F, La Rosa, P, Leclercq, G, Pesiri, V

Mol. Endocrinol. 2012
15956359 Crossroads of estrogen receptor and NF-kappaB signaling

Shi, Q, Biswas, DK, Singh, S, Iglehart, JD, Pardee, AB

Sci. STKE 2005
14534365 Steroid hormone interactions with target cells: cross talk between membrane and nuclear pathways

Farach-Carson, MC, Davis, PJ

J. Pharmacol. Exp. Ther. 2003
17916740 Extranuclear steroid receptors: nature and actions

Hammes, SR, Levin, ER

Endocr. Rev. 2007
16274718 S-palmitoylation modulates estrogen receptor alpha localization and functions

Marino, M, Ascenzi, P, Acconcia, F

Steroids 2006
29980625 Fibronectin rescues estrogen receptor α from lysosomal degradation in breast cancer cells

Thi, K, Toscani, AM, Simian, M, Stefani, FD, Rubashkin, MG, Sampayo, RG, Lakins, JN, Masullo, LA, Bissell, MJ, Hines, WC, Coluccio Leskow, F, Caceres, A, Chialvo, DR, Violi, IL, Weaver, VM

J. Cell Biol. 2018
17037979 Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer

Marker, PC, Hammes, SR, Gioeli, D, Lange, CA

Annu. Rev. Physiol. 2007
15033483 S-palmitoylation modulates human estrogen receptor-alpha functions

Marino, M, Fabozzi, G, Ascenzi, P, Acconcia, F, Visca, P

Biochem. Biophys. Res. Commun. 2004
17424910 Steroid hormone rapid signaling: the pivotal role of S-palmitoylation

Marino, M, Ascenzi, P

IUBMB Life 2006
21354435 Scaffolding proteins mediating membrane-initiated extra-nuclear actions of estrogen receptor

Boonyaratanakornkit, V

Steroids 2011
18657504 Regulation of estrogen rapid signaling through arginine methylation by PRMT1

Leconte, N, Robin-Lespinasse, Y, Gobert-Gosse, S, Bouchekioua-Bouzaghou, K, Goddard, S, Corbo, L, Sentis, S, Treilleux, I, Le Romancer, M

Mol. Cell 2008
22028449 Minireview: Recent advances in extranuclear steroid receptor actions

Hammes, SR, Levin, ER

Endocrinology 2011
12511868 Nongenomic actions of steroid hormones

Wehling, M, Lösel, R

Nat. Rev. Mol. Cell Biol. 2003
22031296 DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors

Levin, ER, Razandi, M, Deschenes, RJ, Pedram, A

Mol. Biol. Cell 2012
21851428 Roles for oestrogen receptor β in adult brain function

Handa, RJ, Wang, JM, Herbison, AE, Ogawa, S

J. Neuroendocrinol. 2012
17535799 A conserved mechanism for steroid receptor translocation to the plasma membrane

Kim, JK, Hughes, CC, Levin, ER, Razandi, M, Sainson, RC, Pedram, A

J. Biol. Chem. 2007
28539435 Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications

Katzenellenbogen, B, Chambon, P, Flouriot, G, Métivier, R, Henrion, D, Katzenellenbogen, J, Arnal, JF, Lenfant, F, Gourdy, P, Fontaine, C, Adlanmerini, M

Physiol. Rev. 2017
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