Reactome | Extra-nuclear estrogen signaling

Extra-nuclear estrogen signaling

Stable Identifier

R-HSA-9009391

DOI

10.3180/R-HSA-9009391.2

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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