Advertisement

Estrogen Receptors in Cell Membranes: Regulation and Signaling

  • Jolanta Saczko
  • Olga Michel
  • Agnieszka Chwiłkowska
  • Ewa Sawicka
  • Justyna Mączyńska
  • Julita Kulbacka
Chapter
Part of the Advances in Anatomy, Embryology and Cell Biology book series (ADVSANAT, volume 227)

Abstract

Estrogens can stimulate the development, proliferation, migration, and survival of target cells. These biological effects are mediated through their action upon the plasma membrane estrogen receptors (ERs). ERs regulate transcriptional processes by nuclear translocation and binding to specific response elements, which leads to the regulation of gene expression. This effect is termed genomic or nuclear. However, estrogens may exert their biological activity also without direct binding to DNA and independently of gene transcription or protein synthesis. This action is called non-genomic or non-nuclear. Through non-genomic mechanisms, estrogens can modify regulatory cascades such as MAPK, P13K, and tyrosine cascade as well as membrane-associated molecules such as ion channels and G-protein-coupled receptors. The recent studies on the mechanisms of estrogen action provide an evidence that non-genomic and genomic effects converge. An example of such convergence is the potential possibility to modulate gene expression through these two independent pathways. The understanding of the plasma membrane estrogen receptors is crucial for the development of novel drugs and therapeutic protocols targeting specific receptor actions.

Notes

Acknowledgments

This work was supported by Statutory Funds of Wroclaw Medical University No.: ST.E130.17.013.

References

  1. Acconcia F, Kumar R (2006) Signaling regulation of genomic and nongenomic functions of estrogen receptors. Cancer Lett 238:1–14CrossRefPubMedGoogle Scholar
  2. Almey A, Milner TA, Brake WG (2015) Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. Horm Behav 74:125–138CrossRefPubMedPubMedCentralGoogle Scholar
  3. Björnström L, Sjoberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19(4):833–842CrossRefPubMedGoogle Scholar
  4. Boonyaratanakornkit V (2011) Scaffolding proteins mediating membrane-initiated extra-nuclear actions of estrogen receptor. Steroids 76:877–884PubMedGoogle Scholar
  5. Boonyaratanakornkit V, Edwards DP (2007) Receptor mechanisms mediating non-genomic actions of sex steroids. Semin Reprod Med 25:139–153CrossRefPubMedGoogle Scholar
  6. Cato AC, Nestl A, Mink S (2002) Rapid actions of steroid receptors in cellular signaling pathways. Sci STKE 138:re9Google Scholar
  7. Cheng SB, Dong J, Pang Y, La Rocca J, Hixon M, Thomas P, Filardo EJ (2014) Anatomical localization and redistribution of G protein -coupled estrogen receptor-1 during the estrus cycle in mouse kidney and specific bindings to estrogen but not aldosterone. Mol Cell Endocrinol 382:950–959CrossRefPubMedGoogle Scholar
  8. Contrò V, Basile JR, Proia P (2015) Sex steroid hormone receptors, their ligands, and nuclear and non-nuclear pathways. AIMS Mol Sci 2:294–310CrossRefGoogle Scholar
  9. Davis PJ, Lin HY, Mousa SA, Luidens MK, Hercbergs AA, Wehling M, Davis FB (2011) Overlapping nongenomic and genomic actions of thyroid hormone and steroids. Steroids 76(9):829–833PubMedGoogle Scholar
  10. Echeverria PC, Picard D (2010) Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility. BBA-Mol Cell Res 1803(6):641–649Google Scholar
  11. Estrada M, Liberona JL, Miranda M, Jaimovich E (2000) Aldosterone- and testosterone –mediated intracellular calcium response in skeletal muscle cell cultures. Am J Physiol Endocrinol Metab 279:132–139Google Scholar
  12. Falkenstein E, Tillmann HC, Christ M, Feuring MM, Wehling M (2000) Multiple actions of steroid hormones – a focus on rapid, nongenomic effects. Pharmacol Rev 52:513–555PubMedGoogle Scholar
  13. Felty Q, Roy D (2005) Estrogen, mitochondria and growth of cancer and non-cancer cells. J Carcinog 4(1):1CrossRefPubMedPubMedCentralGoogle Scholar
  14. Filardo EJ, Quinn JA, Bland KI, Frackelton AR Jr (2000) Estrogen-induces activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 14:1649–1660CrossRefPubMedGoogle Scholar
  15. Gururaj AE, Rayala SK, Vadlamudi RK, Kumar R (2006) Novel mechanisms of resistance to endocrine therapy: genomic and nongenomic considerations. Clin Cancer Res 12(3):1001S–1007SCrossRefPubMedGoogle Scholar
  16. Hammes SR, Davis PJ (2015) Overlapping nongenomic and genomic actions of thyroid hormone and steroids. Best Pract Res Clin Endocrinol Metab 29(4):581–593CrossRefPubMedPubMedCentralGoogle Scholar
  17. Haynes MP, Li L, Sinha D, Russell KS, Hisamoto K, Baron R, Collinge M, Sessa WC, Bender JR (2003) Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J Biol Chem 278(4):2118–2123CrossRefPubMedGoogle Scholar
  18. Jensen EV, Jacobson HI (1962) Basic guides to the mechanism of estrogen action. Recent Prog Horm Res 18(4):387Google Scholar
  19. Kalita K, Lewandowski S, Skrzypczak M, Szymczak S, Tkaczyk M, Kaczmarek L (2004) In: Nowak JZ, Zawilska JB (eds) Receptory estrogenowe. Receptory i mechanizmy przekazywania sygnału. Wydawnictwo Naukowe PWN, Warszawa, pp 604–616Google Scholar
  20. Kampa M, Notas G, Pelekanou V, Troullinaki M, Andrianaki M, Azariadis K, Kampouri E, Lavrentaki K, Castanas E (2012) Early membrane initiated transcriptional effects of estrogens in breast cancer cells: first pharmacological evidence for a novel membrane estrogen receptor element (ERx). Steroids 77:959–967CrossRefPubMedGoogle Scholar
  21. Kurokawa J, Furukawa T (2013) Non-genomic action of sex steroid hormones and cardiac repolarization. Biol Pharm Bull 36(1):8–12CrossRefPubMedGoogle Scholar
  22. Lachowicz-Ochędalska (2005) Membrane receptors for estradiol – new way of biological action. Endokrynol Pol 56(3):322–326PubMedGoogle Scholar
  23. Lee H, Bai W (2002) Regulation of estrogen receptor nuclear export by ligand-induced and p38-mediated receptor phosphorylation. Mol Cell Biol 22(16):5835–5845CrossRefPubMedPubMedCentralGoogle Scholar
  24. Lee-Ming K, Pfaff D (2016) Rapid estrogen actions on ion channels: a survey in search for mechanism. Steroids 111:46–53CrossRefGoogle Scholar
  25. Levin ER, Hammes SR (2016) Nuclear receptors outside the nucleus extranuclear signalling by steroid receptors. Nat Rev Mol Cell Biol 2016:783–797CrossRefGoogle Scholar
  26. Li L, Haynes MP, Bender JR (2003) Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Proc Natl Acad Sci U S A 100:4807–4812CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lin AH, Li RW, Ho EY, Leung GP, Leung SW, Vanhoutte PM, Man RY (2013) Differential ligand binding affinities of human estrogen receptor-alpha isoforms. PLoS One 8(4):e63199CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lu Q, Ebling H, Mittler J, Baur WE, Karas RH (2002) MAP kinase mediates growth factor-induced nuclear translocation of estrogen receptor alpha. FEBS Lett 516(1–3):1–8CrossRefPubMedGoogle Scholar
  29. Marino M, Galluzzo P, Ascenzi P (2006) Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics 7(8):497–508CrossRefPubMedPubMedCentralGoogle Scholar
  30. Migliaccio A, Castoria G, Auricchio F (2007) Src-dependent signalling pathway regulation by sex-steroid hormones: therapeutic implications. Int J Biochem Cell Biol 39:1343–1348CrossRefPubMedGoogle Scholar
  31. Mo Z, Liu M, Yang F, Luo H, Li Z, Tu G, Yang G (2013) GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer. Breast Cancer Res 15(6):R114CrossRefPubMedPubMedCentralGoogle Scholar
  32. Norfleet AM, Thomas ML, Gametchu B, Watson CS (1999) Estrogen receptor-alpha detected on the plasma membrane of aldehyde-fixed GH(3)/B6/F10 rat pituitary tumor cells by enzyme-linked immunocytochemistry. Endocrinology 140:3805–3814CrossRefPubMedGoogle Scholar
  33. O’Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, George SR (1998) Discovery of three novel G-protein-coupled receptor genes. Genomics 47(2):310–313CrossRefPubMedGoogle Scholar
  34. Olde B, Munoz A (2009) GPR30/GPER1: searching for a role in estrogen physiology. Trens Endocrinol Metab 20:409–416CrossRefGoogle Scholar
  35. Ordonez-Moran P, Munoz A (2009) Nuclear receptors. Genomic and non-genomic effects converge. Cell Cycle 8(11):1675–1680CrossRefPubMedGoogle Scholar
  36. Pappas TC, Gametchu B, Watson CS (1995) Membrane estrogen-receptors identified by multiple antibody labeling and impeded-ligand binding. FASEB J 9:404–410PubMedGoogle Scholar
  37. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Cobb MH (2001) Mitogen – activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:153–183PubMedGoogle Scholar
  38. Pedram A, Razandi M, Lewis M, Hammes S, Levin ER (2014) Membrane-localized estrogen receptor α is required for normal organ development and function. Dev Cell 29(4):482–490CrossRefPubMedPubMedCentralGoogle Scholar
  39. Prossnitz ER, Maggiolini M (2009) Mechanisms of estrogen signaling and gene expression via GPR30. Mol Cell Endocrinol 308:32–38CrossRefPubMedPubMedCentralGoogle Scholar
  40. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307:1625–1630CrossRefPubMedGoogle Scholar
  41. Riggio M, Polo ML, Blaustein M, Colman-Lerner A, Lüthy I, Lanari C, Novaro V (2012) PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer. Carcinogenesis 33(3):509–518CrossRefPubMedGoogle Scholar
  42. Schmidt BMW, Gerdes D, Feuring M, Falkenstein E, Christ M, Wehling M (2000) Rapid, nongenomic steroid actions: a new age? Front Neuroendocrinol 21:57–94CrossRefPubMedGoogle Scholar
  43. Simoncini T, Genazzani AR (2003) Non-genomic actions of sex steroid hormones. Eur J Endocrinol 148:281–292CrossRefPubMedGoogle Scholar
  44. Simoncini T, Mannella P, Fornari L, Caruso A, Varone G, Genazzani AR (2004) Genomic and non-genomic effects of estrogens on endothelial cells. Steroids 69:537–542CrossRefPubMedGoogle Scholar
  45. Soltysik K, Czekaj P (2013) Membrane estrogen receptors – is it an alternative way of estrogen action? J Physiol Pharmacol 64:129–142PubMedGoogle Scholar
  46. Świtalska M, Strządała L (2007) Niegenomowe działanie estrogenów. Postępy Hig Med Dośw 61:541–547Google Scholar
  47. Szego CM, Davis JS (1967) Adenosine 3′,5′-monophosphate in rat uterus – acute elevation by estrogen. Proc Natl Acad Sci U S A 58(4):1711–1718CrossRefPubMedPubMedCentralGoogle Scholar
  48. Toran-Allerand CD, Guan XP, MacLusky NJ, Horvath TL, Diano S, Singh M, Connolly ES, Nethrapalli IS, Tinnikov AA (2002) ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J Neurosci 22:8391–8401PubMedGoogle Scholar
  49. Vadlamudi RK, Manavathi B, Balasenthil S, Nair SS, Yang Z, Sahin AA, Kumar R (2005) Functional implications of altered subcellular localization of PELP1 in breast cancer cells. Cancer Res 65(17):7724–7732CrossRefPubMedPubMedCentralGoogle Scholar
  50. Vrtačnik P, Ostanek B, Mencej-Bedrač S, Marc J (2014) The many faces of estrogen signaling. Biochem Med 24(3):329–342CrossRefGoogle Scholar
  51. Watson CS, Campbell CH, Gametchu B (2002) The dynamic and elusive membrane estrogen receptor-alpha. Steroids 67:429–437CrossRefPubMedGoogle Scholar
  52. Watson CS, Jeng YJ, Guptarak J (2011) Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways. J Steroid Biochem Mol Biol 127(1–2):44–50CrossRefPubMedPubMedCentralGoogle Scholar
  53. Wei C, Cao Y, Yang X, Zheng Z, Guan K, Wang Q, Tai Y, Zhang Y, Ma S, Cao Y, GeX XC, Li J, Yan H, Ling Y, Song T, Zhu L, Zhang B, Xu Q, Hu C, Bian XW, He X, Zhong H (2014) Elevated expression of TANK-binding kinase 1 enhances tamoxifen resistance in breast cancer. Proc Natl Acad Sci U S A 111(5):E601–E610CrossRefPubMedPubMedCentralGoogle Scholar
  54. Wróbel AM, Gregoraszczuk EŁ (2015) Action of methyl-, propyl- and butylparaben on GPR30 gene and protein expression, cAMP levels and activation of ERK1/2 and PI3K/Akt signaling pathways in MCF-7 breast cancer cells and MCF-10A non-transformed breast epithelial cells. Toxicol Lett 238(2):110–116CrossRefPubMedGoogle Scholar
  55. Yamakawa K, Arita J (2004) Cross-talk between the estrogen receptor-, protein kinase A-, and mitogen-activated protein kinase-mediated signaling pathways in the regulation of lactotroph proliferation in primary culture. J Steroid Biochem Mol Biol 88(2):123–130CrossRefPubMedGoogle Scholar
  56. Yue W, Wang JP, Conaway M, Masamura S, Li Y, Santen RJ (2002) Activation of the MAPK pathway enhances sensitivity of MCF-7 breast cancer cells to the mitogenic effect of estradiol. Endocrinology 143(9):3221–3229CrossRefPubMedGoogle Scholar
  57. Zhang DP, Trudeau VL (2006) Integration of membrane and nuclear estrogen receptor signaling. Comp Biochem Physiol A Mol Integr Physiol 144(3):306–315CrossRefPubMedGoogle Scholar
  58. Zielniok K, Gajewska M, Motyl T (2014) Molecular actions of 17 beta-estradiol and progesterone and their relationship with cellular signaling pathways. Postepy Hig Med Dosw 68:777–792CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Jolanta Saczko
    • 1
  • Olga Michel
    • 1
  • Agnieszka Chwiłkowska
    • 1
  • Ewa Sawicka
    • 2
  • Justyna Mączyńska
    • 1
  • Julita Kulbacka
    • 1
  1. 1.Department of Medical BiochemistryWroclaw Medical UniversityWroclawPoland
  2. 2.Department of ToxicologyWroclaw Medical UniversityWroclawPoland

Personalised recommendations