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Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors

Nature Reviews Molecular Cell Biology volume 17, pages 783–797 (2016)Cite this article

Subjects

Key Points

  • Steroid receptors classically function in the nucleus, regulating the expression of genes that are important for a wide range of cellular functions.

  • It has now become clear that many classic steroid receptors also localize to other cellular compartments (including, prominently, the plasma membrane) to activate various signalling pathways.

  • Signalling from membrane-localized steroid receptors can elicit non-genomic responses, such as G protein and kinase signalling.

  • Steroid receptor signalling from the membrane can also be involved in the regulation of gene expression, sometimes by engaging in crosstalk with nuclear pools of the respective receptor.

  • Membrane-initiated steroid signalling has been shown to have various physiological functions and has been associated with the development and propagation of cancer.

  • Transgenic mice that selectively express only one functional oestrogen receptor-α pool — either membrane or nuclear — display phenotypes that overlap significantly with those of mice completely lacking oestrogen receptor-α, indicating that both pools are necessary for most oestrogen-dependent processes. More broadly, it can be concluded that extranuclear steroid signalling is required for full steroid hormone action during development and organ homeostasis.

Abstract

Steroid hormone receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most steroid receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of steroid hormone signalling and its roles in health and disease.

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Figure 1: Nuclear steroid signalling.
Figure 2: Events dictating trafficking of oestrogen receptor-α to and from the plasma membrane and its signal transduction.
Figure 3: Membrane-localized steroid receptors can modulate gene expression in the nucleus.
Figure 4: Membrane steroid signalling in the regulation of metabolism, organ homeostasis and organogenesis.

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References

  1. Barkhem, T., Nilsson, S. & Gustafsson, J. A. Molecular mechanisms, physiological consequences and pharmacological implications of estrogen receptor action. Am. J. Pharmacogenomics 4, 19–28 (2004).

    CAS  PubMed  Google Scholar 

  2. Selye, H. Stress and the general adaptation syndrome. Br. Med. J. 1, 1383–1392 (1950).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lykissas, E. D., Kourounakis, P. & Selye, H. Hepatic intracellular distribution of pregnenolone-16α-carbonitrile and its influence on adenyl cyclase activity in rat liver cells. Res. Commun. Chem. Pathol. Pharmacol. 19, 173–176 (1978).

    CAS  PubMed  Google Scholar 

  4. Spaziani, E. & Szego, C. M. Early effects of estradiol and cortisol on water and electrolyte shifts in the uterus of the immature rat. Am. J. Physiol. 197, 355–359 (1959).

    CAS  PubMed  Google Scholar 

  5. Szego, C. M. & Davis, J. S. Adenosine 3′,5′-monophosphate in rat uterus: acute elevation by estrogen. Proc. Natl Acad. Sci. USA 58, 1711–1718 (1967).

    CAS  PubMed  Google Scholar 

  6. Pietras, R. J. & Szego, C. M. Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells. Nature 265, 69–72 (1977).Demonstrates clearly for the first time the presence of steroid-binding sites at the plasma membrane.

    CAS  PubMed  Google Scholar 

  7. Wang, Z. Y., Seto, H., Fujioka, S., Yoshida, S. & Chory, J. BRI1 is a critical component of a plasma-membrane receptor for plant steroids. Nature 410, 380–383 (2001).

    CAS  PubMed  Google Scholar 

  8. Hammes, S. R. & Levin, E. R. Extranuclear steroid receptors: nature and actions. Endocr. Rev. 28, 726–741 (2007).

    CAS  PubMed  Google Scholar 

  9. Sen, A. et al. Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation. J. Clin. Invest. 122, 2469–2481 (2012).Provides the first demonstration of collaborative extranuclear and nuclear AR signalling.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sen, A. et al. Paxillin regulates androgen- and epidermal growth factor-induced MAPK signaling and cell proliferation in prostate cancer cells. J. Biol. Chem. 285, 28787–28795 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Migliaccio, A. et al. Steroid-induced androgen receptor-oestradiol receptor β-Src complex triggers prostate cancer cell proliferation. EMBO J. 19, 5406–5417 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Migliaccio, A. et al. Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J. 17, 2008–2018 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Daniel, A. R. et al. Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes. Oncogene 34, 506–515 (2015).

    CAS  PubMed  Google Scholar 

  14. McNamara, K. M., Moore, N. L., Hickey, T. E., Sasano, H. & Tilley, W. D. Complexities of androgen receptor signalling in breast cancer. Endocr. Relat. Cancer 21, T161–T181 (2014).

    CAS  PubMed  Google Scholar 

  15. Simons, S. S. Jr, Edwards, D. P. & Kumar, R. Minireview: dynamic structures of nuclear hormone receptors: new promises and challenges. Mol. Endocrinol. 28, 173–182 (2014).

    PubMed  Google Scholar 

  16. Burns, K. A., Li, Y., Arao, Y., Petrovich, R. M. & Korach, K. S. Selective mutations in estrogen receptor α D-domain alters nuclear translocation and non-estrogen response element gene regulatory mechanisms. J. Biol. Chem. 286, 12640–12649 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Shiau, A. K. et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95, 927–937 (1998).

    CAS  PubMed  Google Scholar 

  18. Lubahn, D. B. et al. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc. Natl Acad. Sci. USA 90, 11162–11166 (1993).

    CAS  PubMed  Google Scholar 

  19. Lydon, J. P. et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 9, 2266–2278 (1995).

    CAS  PubMed  Google Scholar 

  20. Pappas, T. C., Gametchu, B. & Watson, C. S. Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding. FASEB J. 9, 404–410 (1995).

    CAS  PubMed  Google Scholar 

  21. Norfleet, A. M., Thomas, M. L., Gametchu, B. & Watson, C. S. Estrogen receptor-α detected on the plasma membrane of aldehyde-fixed GH3/B6/F10 rat pituitary tumor cells by enzyme-linked immunocytochemistry. Endocrinology 140, 3805–3814 (1999).

    CAS  PubMed  Google Scholar 

  22. Razandi, M., Pedram, A., Greene, G. L. & Levin, E. R. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERα and ERβ expressed in Chinese hamster ovary cells. Mol. Endocrinol. 13, 307–319 (1999).

    CAS  PubMed  Google Scholar 

  23. Pedram, A., Razandi, M. & Levin, E. R. Nature of functional estrogen receptors at the plasma membrane. Mol. Endocrinol. 20, 1996–2009 (2006).

    CAS  PubMed  Google Scholar 

  24. Kousteni, S. et al. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 298, 843–846 (2002).Reveals that transcription-independent oestrogen signalling is important for normal bone formation.

    CAS  PubMed  Google Scholar 

  25. Li, L., Haynes, M. P. & Bender, J. R. Plasma membrane localization and function of the estrogen receptor α variant (ER46) in human endothelial cells. Proc. Natl Acad. Sci. USA 100, 4807–4812 (2003).

    CAS  PubMed  Google Scholar 

  26. Wang, Z. et al. A variant of estrogen receptor-α, hER-α36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling. Proc. Natl Acad. Sci. USA 103, 9063–9068 (2006).

    CAS  PubMed  Google Scholar 

  27. Nilsson, S. et al. Mechanisms of estrogen action. Physiol. Rev. 81, 1535–1565 (2001).

    CAS  PubMed  Google Scholar 

  28. Flouriot, G., Griffin, C., Kenealy, M., Sonntag-Buck, V. & Gannon, F. Differentially expressed messenger RNA isoforms of the human estrogen receptor-α gene are generated by alternative splicing and promoter usage. Mol. Endocrinol. 12, 1939–1954 (1998).

    CAS  PubMed  Google Scholar 

  29. Pedram, A. et al. A conserved mechanism for steroid receptor translocation to the plasma membrane. J. Biol. Chem. 282, 22278–22288 (2007).

    CAS  PubMed  Google Scholar 

  30. Lutz, L. B. et al. Evidence that androgens are the primary steroids produced by Xenopus laevis ovaries and may signal through the classical androgen receptor to promote oocyte maturation. Proc. Natl Acad. Sci. USA 98, 13728–13733 (2001).

    CAS  PubMed  Google Scholar 

  31. Lutz, L. B., Kim, B., Jahani, D. & Hammes, S. R. G protein βγ subunits inhibit nongenomic progesterone-induced signaling and maturation in Xenopus laevis oocytes. Evidence for a release of inhibition mechanism for cell cycle progression. J. Biol. Chem. 275, 41512–41520 (2000).Shows that androgens modulate G protein signalling at the cell membrane.

    CAS  PubMed  Google Scholar 

  32. Evaul, K., Jamnongjit, M., Bhagavath, B. & Hammes, S. R. Testosterone and progesterone rapidly attenuate plasma membrane Gβγ-mediated signaling in Xenopus laevis oocytes by signaling through classical steroid receptors. Mol. Endocrinol. 21, 186–196 (2007).

    CAS  PubMed  Google Scholar 

  33. Sen, A. & Hammes, S. R. Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Mol. Endocrinol. 24, 1393–1403 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sen, A. et al. Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Proc. Natl Acad. Sci. USA 111, 3008–3013 (2014).

    CAS  PubMed  Google Scholar 

  35. Ballare, C. et al. Two domains of the progesterone receptor interact with the estrogen receptor and are required for progesterone activation of the c-Src/Erk pathway in mammalian cells. Mol. Cell. Biol. 23, 1994–2008 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Boonyaratanakornkit, V. et al. Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases. Mol. Cell 8, 269–280 (2001).

    CAS  PubMed  Google Scholar 

  37. Nemere, I. et al. Ribozyme knockdown functionally links a 1,25(OH)2D3 membrane binding protein (1,25D3-MARRS) and phosphate uptake in intestinal cells. Proc. Natl Acad. Sci. USA 101, 7392–7397 (2004).

    CAS  PubMed  Google Scholar 

  38. Mizwicki, M. T. & Norman, A. W. The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling. Sci. Signal. 2, re4 (2009).

    PubMed  Google Scholar 

  39. Kalyanaraman, H. et al. Nongenomic thyroid hormone signaling occurs through a plasma membrane-localized receptor. Sci. Signal. 7, ra48 (2014).Provides the first description of a membrane-localized, truncated form of THRα.

    PubMed  PubMed Central  Google Scholar 

  40. Martin, N. P. et al. A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo. Endocrinology 155, 3713–3724 (2014).Describes the functional effects of rapid signalling by extranuclear THRβ.

    PubMed  PubMed Central  Google Scholar 

  41. Filardo, E. J., Quinn, J. A., Bland, K. I. & Frackelton, A. R. Jr. Estrogen-induced 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, 1649–1660 (2000).

    CAS  PubMed  Google Scholar 

  42. Thomas, P., Pang, Y., Filardo, E. J. & Dong, J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 146, 624–632 (2005).

    CAS  PubMed  Google Scholar 

  43. Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B. & Prossnitz, E. R. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307, 1625–1630 (2005).

    CAS  PubMed  Google Scholar 

  44. Otto, C. et al. G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol. Endocrinology 149, 4846–4856 (2008).

    CAS  PubMed  Google Scholar 

  45. Isensee, J. et al. Expression pattern of G protein-coupled receptor 30 in LacZ reporter mice. Endocrinology 150, 1722–1730 (2009).

    CAS  PubMed  Google Scholar 

  46. Otto, C. et al. GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biol. Reprod. 80, 34–41 (2009).

    CAS  PubMed  Google Scholar 

  47. Albanito, L. et al. G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17β-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res. 67, 1859–1866 (2007).

    CAS  PubMed  Google Scholar 

  48. Madak-Erdogan, Z. et al. Nuclear and extranuclear pathway inputs in the regulation of global gene expression by estrogen receptors. Mol. Endocrinol. 22, 2116–2127 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Takabe, K. et al. Estradiol induces export of sphingosine 1-phosphate from breast cancer cells via ABCC1 and ABCG2. J. Biol. Chem. 285, 10477–10486 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Gaudet, H. M., Cheng, S. B., Christensen, E. M. & Filardo, E. J. The G-protein coupled estrogen receptor, GPER: the inside and inside-out story. Mol. Cell. Endocrinol. 3, 207–219 (2015).Reviews recent research on the functions of GPER1.

    Google Scholar 

  51. Engmann, L., Losel, R., Wehling, M. & Peluso, J. J. Progesterone regulation of human granulosa/luteal cell viability by an RU486-independent mechanism. J. Clin. Endocrinol. Metab. 91, 4962–4968 (2006).

    CAS  PubMed  Google Scholar 

  52. Friel, A. M. et al. Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors. Cancer Lett. 356, 434–442 (2015).

    CAS  PubMed  Google Scholar 

  53. Li, X. et al. Progesterone receptor membrane component-1 regulates hepcidin biosynthesis. J. Clin. Invest. 126, 389–401 (2016).Demonstrates the importance of PGRMC1 for the regulation of iron metabolism.

    PubMed  Google Scholar 

  54. Zhu, Y., Bond, J. & Thomas, P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc. Natl Acad. Sci. USA 100, 2237–2242 (2003).

    CAS  PubMed  Google Scholar 

  55. Zhu, Y., Rice, C. D., Pang, Y., Pace, M. & Thomas, P. Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc. Natl Acad. Sci. USA 100, 2231–2236 (2003).

    CAS  PubMed  Google Scholar 

  56. Sleiter, N. et al. Progesterone receptor A (PRA) and PRB-independent effects of progesterone on gonadotropin-releasing hormone release. Endocrinology 150, 3833–3844 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Pi, M. et al. Structural and functional evidence for testosterone activation of GPRC6A in peripheral tissues. Mol. Endocrinol. 29, 1759–1773 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Pi, M., Parrill, A. L. & Quarles, L. D. GPRC6A mediates the non-genomic effects of steroids. J. Biol. Chem. 285, 39953–39964 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Razandi, M., Pedram, A., Merchenthaler, I., Greene, G. L. & Levin, E. R. Plasma membrane estrogen receptors exist and functions as dimers. Mol. Endocrinol. 18, 2854–2865 (2004).

    CAS  PubMed  Google Scholar 

  60. Pedram, A., Razandi, M., Deschenes, R. J. & Levin, E. R. DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors. Mol. Biol. Cell 23, 188–199 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Galluzzo, P., Caiazza, F., Moreno, S. & Marino, M. Role of ERβ palmitoylation in the inhibition of human colon cancer cell proliferation. Endocr. Relat. Cancer 14, 153–167 (2007).

    CAS  PubMed  Google Scholar 

  62. Acconcia, F. et al. Palmitoylation-dependent estrogen receptor α membrane localization: regulation by 17β-estradiol. Mol. Biol. Cell 16, 231–237 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Razandi, M., Pedram, A. & Levin, E. R. Heat shock protein 27 is required for sex steroid receptor trafficking to and functioning at the plasma membrane. Mol. Cell. Biol. 30, 3249–3261 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Peffer, M. E. et al. Caveolin-1 regulates genomic action of the glucocorticoid receptor in neural stem cells. Mol. Cell. Biol. 34, 2611–2623 (2014).

    PubMed  PubMed Central  Google Scholar 

  65. Razandi, M., Oh, P., Pedram, A., Schnitzer, J. & Levin, E. R. ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions. Mol. Endocrinol. 16, 100–115 (2002).

    CAS  PubMed  Google Scholar 

  66. Kumar, P. et al. Direct interactions with Gαi and Gβγ mediate nongenomic signaling by estrogen receptor α. Mol. Endocrinol. 21, 1370–1380 (2007).

    CAS  PubMed  Google Scholar 

  67. Razandi, M., Pedram, A., Park, S. T. & Levin, E. R. Proximal events in signaling by plasma membrane estrogen receptors. J. Biol. Chem. 278, 2701–2712 (2003).

    CAS  PubMed  Google Scholar 

  68. Song, R. X. et al. The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane. Proc. Natl Acad. Sci. USA 101, 2076–2081 (2004).

    CAS  PubMed  Google Scholar 

  69. Galluzzo, P., Ascenzi, P., Bulzomi, P. & Marino, M. The nutritional flavanone naringenin triggers antiestrogenic effects by regulating estrogen receptor α-palmitoylation. Endocrinology 149, 2567–2575 (2008).

    CAS  PubMed  Google Scholar 

  70. Totta, P., Pesiri, V., Marino, M. & Acconcia, F. Lysosomal function is involved in 17β-estradiol-induced estrogen receptor α degradation and cell proliferation. PLoS ONE 9, e94880 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Faivre, E. J. & Lange, C. A. Progesterone receptors upregulate Wnt-1 to induce epidermal growth factor receptor transactivation and c-Src-dependent sustained activation of Erk1/2 mitogen-activated protein kinase in breast cancer cells. Mol. Cell. Biol. 27, 466–480 (2007).

    CAS  PubMed  Google Scholar 

  72. Thomas, W. & Harvey, B. J. Mechanisms underlying rapid aldosterone effects in the kidney. Annu. Rev. Physiol. 73, 335–357 (2011).

    CAS  PubMed  Google Scholar 

  73. Grossmann, C., Freudinger, R., Mildenberger, S., Husse, B. & Gekle, M. EF domains are sufficient for nongenomic mineralocorticoid receptor actions. J. Biol. Chem. 283, 7109–7116 (2008).

    CAS  PubMed  Google Scholar 

  74. Le Moellic, C. et al. Early nongenomic events in aldosterone action in renal collecting duct cells: PKCα activation, mineralocorticoid receptor phosphorylation, and cross-talk with the genomic response. J. Am. Soc. Nephrol. 15, 1145–1160 (2004).

    CAS  PubMed  Google Scholar 

  75. Weigel, N. L. & Moore, N. L. Kinases and protein phosphorylation as regulators of steroid hormone action. Nucl. Recept. Signal. 5, e005 (2007).

    PubMed  PubMed Central  Google Scholar 

  76. York, B. et al. Reprogramming the posttranslational code of SRC-3 confers a switch in mammalian systems biology. Proc. Natl Acad. Sci. USA 107, 11122–11127 (2010).

    CAS  PubMed  Google Scholar 

  77. Zheng, F. F., Wu, R. C., Smith, C. L. & O'Malley, B. W. Rapid estrogen-induced phosphorylation of the SRC-3 coactivator occurs in an extranuclear complex containing estrogen receptor. Mol. Cell. Biol. 25, 8273–8284 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Jonas, B. A. & Privalsky, M. L. SMRT and N-CoR corepressors are regulated by distinct kinase signaling pathways. J. Biol. Chem. 279, 54676–54686 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Trevino, L. S. & Weigel, N. L. Phosphorylation: a fundamental regulator of steroid receptor action. Trends Endocrinol. Metab. 24, 515–524 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Wong, W. P. et al. Extranuclear estrogen receptor-α stimulates NeuroD1 binding to the insulin promoter and favors insulin synthesis. Proc. Natl Acad. Sci. USA 107, 13057–13062 (2010).

    CAS  PubMed  Google Scholar 

  81. Vazquez-Martin, A. et al. Reprogramming of non-genomic estrogen signaling by the stemness factor SOX2 enhances the tumor-initiating capacity of breast cancer cells. Cell Cycle 12, 3471–3477 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Vares, G. et al. Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells. Cancer Lett. 362, 167–173 (2015).

    CAS  PubMed  Google Scholar 

  83. Pedram, A., Razandi, M., Blumberg, B. & Levin, E. R. Membrane and nuclear estrogen receptor α collaborate to suppress adipogenesis but not triglyceride content. FASEB J. 30, 230–240 (2016).Indicates the collaboration of membrane and nuclear ERα to suppress bone marrow-derived progenitor cells from committing to the adipocyte lineage.

    CAS  PubMed  Google Scholar 

  84. Pedram, A. et al. Estrogen reduces lipid content in the liver exclusively from membrane receptor signaling. Sci. Signal. 6, ra36 (2013).Provides in vivo evidence that important lipid-suppressing functions of oestrogen are dependent entirely on membrane ERα signalling.

    PubMed  Google Scholar 

  85. Tiano, J. P. et al. Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes. J. Clin. Invest. 121, 3331–3342 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Tiano, J. P. & Mauvais-Jarvis, F. Molecular mechanisms of estrogen receptors' suppression of lipogenesis in pancreatic β-cells. Endocrinology 153, 2997–3005 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Bredfeldt, T. G. et al. Xenoestrogen-induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Mol. Endocrinol. 24, 993–1006 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Pedram, A., Razandi, M., Lewis, M., Hammes, S. & Levin, E. R. Membrane-localized estrogen receptor α is required for normal organ development and function. Dev. Cell 29, 482–490 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Pedram, A. et al. Estrogen regulates histone deacetylases to prevent cardiac hypertrophy. Mol. Biol. Cell 24, 3805–3818 (2013).

    PubMed  PubMed Central  Google Scholar 

  90. Masui, K., Cavenee, W. K. & Mischel, P. S. mTORC2 in the center of cancer metabolic reprogramming. Trends Endocrinol. Metab. 25, 364–373 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Bhatt, S., Xiao, Z., Meng, Z. & Katzenellenbogen, B. S. Phosphorylation by p38 mitogen-activated protein kinase promotes estrogen receptor α turnover and functional activity via the SCF(Skp2) proteasomal complex. Mol. Cell. Biol. 32, 1928–1943 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Reid, G. et al. Cyclic, proteasome-mediated turnover of unliganded and liganded ERα on responsive promoters is an integral feature of estrogen signaling. Mol. Cell 11, 695–707 (2003).

    CAS  PubMed  Google Scholar 

  93. Gutierrez-Mecinas, M. et al. Long-lasting behavioral responses to stress involve a direct interaction of glucocorticoid receptors with ERK1/2–MSK1–Elk-1 signaling. Proc. Natl Acad. Sci. USA 108, 13806–13811 (2011).

    CAS  PubMed  Google Scholar 

  94. Nahar, J. et al. Rapid nongenomic glucocorticoid actions in male mouse hypothalamic neuroendocrine cells are dependent on the nuclear glucocorticoid receptor. Endocrinology 156, 2831–2842 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Pedram, A. et al. Developmental phenotype of a membrane only estrogen receptor α (MOER) mouse. J. Biol. Chem. 284, 3488–3495 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Mauvais-Jarvis, F., Clegg, D. J. & Hevener, A. L. The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34, 309–338 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Soriano, S. et al. Rapid regulation of KATP channel activity by 17β-estradiol in pancreatic β-cells involves the estrogen receptor β and the atrial natriuretic peptide receptor. Mol. Endocrinol. 23, 1973–1982 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. O'Mahony, F., Razandi, M., Pedram, A., Harvey, B. J. & Levin, E. R. Estrogen modulates metabolic pathway adaptation to available glucose in breast cancer cells. Mol. Endocrinol. 26, 2058–2070 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Fierz, Y., Novosyadlyy, R., Vijayakumar, A., Yakar, S. & LeRoith, D. Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression. Diabetes 59, 686–693 (2010).

    CAS  PubMed  Google Scholar 

  100. Novosyadlyy, R. et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res. 70, 741–751 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Pedram, A., Razandi, M., Aitkenhead, M. & Levin, E. R. Estrogen inhibits cardiomyocyte hypertrophy in vitro. Antagonism of calcineurin-related hypertrophy through induction of MCIP1. J. Biol. Chem. 280, 26339–26348 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Pedram, A., Razandi, M., O'Mahony, F., Lubahn, D. & Levin, E. R. Estrogen receptor-β prevents cardiac fibrosis. Mol. Endocrinol. 24, 2152–2165 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Chen, Z. et al. Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J. Clin. Invest. 103, 401–406 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Adlanmerini, M. et al. Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc. Natl Acad. Sci. USA 111, E283–E290 (2014).

    CAS  PubMed  Google Scholar 

  105. Umetani, M. et al. 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat. Med. 13, 1185–1192 (2007).

    CAS  PubMed  Google Scholar 

  106. Umetani, M. & Shaul, P. W. 27-Hydroxycholesterol: the first identified endogenous SERM. Trends Endocrinol. Metab. 22, 130–135 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Wu, Q. et al. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep. 5, 637–645 (2013).Provides the first report of breast tumour-produced 27HC and a potential role in aromatase-inhibitor therapy for this malignancy.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Ishikawa, T. et al. LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity. J. Clin. Invest. 123, 3488–3497 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lefterova, M. I., Haakonsson, A. K., Lazar, M. A. & Mandrup, S. PPARγ and the global map of adipogenesis and beyond. Trends Endocrinol. Metab. 25, 293–302 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Choi, J., Park, S. & Sockanathan, S. Activated retinoid receptors are required for the migration and fate maintenance of subsets of cortical neurons. Development 141, 1151–1160 (2014).

    CAS  PubMed  Google Scholar 

  111. Lee, C. T. et al. The nuclear orphan receptor COUP-TFII is required for limb and skeletal muscle development. Mol. Cell. Biol. 24, 10835–10843 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Noguchi, K. K., Lau, K., Smith, D. J., Swiney, B. S. & Farber, N. B. Glucocorticoid receptor stimulation and the regulation of neonatal cerebellar neural progenitor cell apoptosis. Neurobiol. Dis. 43, 356–363 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Atwood, C. S. et al. Progesterone induces side-branching of the ductal epithelium in the mammary glands of peripubertal mice. J. Endocrinol. 167, 39–52 (2000).

    CAS  PubMed  Google Scholar 

  114. Brisken, C. & O'Malley, B. Hormone action in the mammary gland. Cold Spring Harb. Perspect. Biol. 2, a003178 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Han, S. J. et al. Estrogen receptor β modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell 163, 960–974 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Pedram, A., Razandi, M., Wallace, D. C. & Levin, E. R. Functional estrogen receptors in the mitochondria of breast cancer cells. Mol. Biol. Cell 17, 2125–2137 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Adzic, M. et al. Brain region- and sex-specific modulation of mitochondrial glucocorticoid receptor phosphorylation in fluoxetine treated stressed rats: effects on energy metabolism. Psychoneuroendocrinology 38, 2914–2924 (2013).

    CAS  PubMed  Google Scholar 

  118. Lee, S. R. et al. Glucocorticoids and their receptors: insights into specific roles in mitochondria. Prog. Biophys Mol. Biol. 112, 44–54 (2013).Highlights the functions of GR in mitochondria.

    CAS  PubMed  Google Scholar 

  119. Simoes, D. C. et al. Glucocorticoid and estrogen receptors are reduced in mitochondria of lung epithelial cells in asthma. PLoS ONE 7, e39183 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Razandi, M., Pedram, A., Jordan, V. C., Fuqua, S. & Levin, E. R. Tamoxifen regulates cell fate through mitochondrial estrogen receptor β in breast cancer. Oncogene 32, 3274–3285 (2013).

    CAS  PubMed  Google Scholar 

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Acknowledgements

E.R.L. is supported by funding from the US National Institutes of Health (NIH; grant 3R01CA100366) and the US Veterans Administration (grant 5I01BX002316), and S.R.H. is supported by grants from the NIH (R01GM101709-01 and R01CA193583-01).

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Authors and Affiliations

  1. Department of Medicine and Biochemistry, University of California, Irvine and the Long Beach VA Medical Center, 90822, California, USA

    Ellis R. Levin

  2. Departments of Medicine and Pharmacology, University of Rochester, Rochester, 14642, New York, USA

    Stephen R. Hammes

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  1. Ellis R. Levin
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Correspondence to Ellis R. Levin or Stephen R. Hammes.

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PowerPoint slides

Glossary

Co-regulators

Proteins that complex with other transcriptional regulatory proteins to alter gene expression.

Epigenetic regulation

Modification of gene expression that does not involve the modification of the genetic code itself.

G protein

Guanine nucleotide-binding protein that initiates signal transduction.

Ovarian granulosa cells

Cells that surround and support the oocyte in ovarian follicles and contribute to steroidogenesis and follicle growth.

Caveolae

Lipid-containing invaginations at and within the plasma membrane in which caveolins serve as structural coat proteins and as scaffolds for many signalling molecules.

Osteocytes

Multinucleated bone cells that break down bone matrix.

Osteoblasts

Bone cells that generate new bone matrix.

Leydig cells

Androgen-producing cells in the testes.

Corpus luteum

A hormone-secreting structure that develops from the remains of the ovarian follicle after ovulation.

Enhancers

Short regions of DNA that are bound by proteins (transcriptional regulators) to stimulate transcription.

SH3 domains

Src-homology domains that are sites of physical protein–protein interactions.

Histone acetyltransferases

Enzymes that add acetyl groups to proteins, most notably histones, thereby contributing to epigenetic regulation of gene expression.

Ductal branching

The extending of hollow milk ducts through the mammary glands (like branches on a tree).

Histone deacetylases

(HDACs). Enzymes that remove acetyl groups from histones, thereby contributing to epigenetic regulation of gene expression proteins.

Chromatin writers, erasers and readers

Proteins that, respectively, place, remove and interpret chemical modifications on histone proteins.

Gap junction

A specialized intercellular connection between cells.

Dentate gyrus

Region of the hippocampus in the brain that is thought to regulate memories and other functions.

Hypothalamus

Region of the brain that links the nervous system to the endocrine system by signalling with the pituitary.

Selective oestrogen receptor modulator

(SERM). A molecule similar but distinct from oestradiol that interacts with oestrogen receptors as either an agonist or an antagonist, depending on the tissue context.

Aortic ring

An angiogenesis model using cultured aortic cells.

Carotid artery

An artery coming off the aorta that supplies the brain with blood.

Endometriosis

Unregulated proliferation of the uterine endometrium outside the uterus.

Ovarian follicles

Spheroid regions within the ovary that each contain and nurture an oocyte until ovulation and also produce sex steroids.

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Levin, E., Hammes, S. Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors. Nat Rev Mol Cell Biol 17, 783–797 (2016). https://doi.org/10.1038/nrm.2016.122

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