Semin Reprod Med 2007; 25(3): 139-153
DOI: 10.1055/s-2007-973427
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Receptor Mechanisms Mediating Non-Genomic Actions of Sex Steroids

Viroj Boonyaratanakornkit1 , Dean P. Edwards1 , 2
  • 1Department of Molecular and Cellular Biology, Houston, Texas
  • 2Pathology, Baylor College of Medicine, Houston, Texas
Further Information

Publication History

Publication Date:
20 April 2007 (online)


Sex steroid hormones, including estrogen, progesterone, and androgen, mediate their biological effects on cell proliferation, differentiation, and homeostasis through their respective nuclear receptors. In addition to functioning as ligand-activated nuclear transcription factors to regulate gene transcription, these receptors also have been shown to mediate rapid activation of non-genomic signaling pathways independent of their transcriptional activity. Despite the fact that non-genomic effects of sex steroids have been observed since more than three decades ago, the receptor mechanisms mediating these rapid effects still are not well understood. A subpopulation of nuclear steroid receptors localized to the cell membrane or cytoplasm has been proposed to mediate steroid hormone activation of signaling pathways; however, novel membrane receptors unrelated to nuclear receptors have also been implicated. This review focuses on recent advances in our understanding of the nature of the receptors and mechanisms responsible for rapid non-genomic signaling actions of sex steroids, including novel membrane receptors and interactions of nuclear steroid receptors with membrane and cytoplasmic signaling molecules such as adapter proteins, G proteins, ion channels, and protein kinases. A better definition of receptor mechanisms involved in mediating activation of non-genomic signaling pathways is important to our overall understanding of the biology of steroid hormones.


  • 1 Mangelsdorf D J, Tummel C, Beato M et al.. The nuclear receptor superfamily: the second decade.  Cell. 1995;  83 835-839
  • 2 Tsai M, O'Malley B. Molecular mechanisms of action of steroid/thyroid receptor superfamily members.  Annu Rev Biochem. 1994;  63 451-486
  • 3 McKenna N J, Lanz R B, O'Malley B W. Nuclear receptor coregulators: cellular and molecular biology.  Endocr Rev. 1999;  20(3) 321-344
  • 4 Ahrens-Fath I, Politz O, Geserick C, Haendler B. Androgen receptor function is modulated by the tissue-specific AR45 variant.  FEBS J. 2005;  272 74-84
  • 5 Kuiper G GJM, Enmark E, Pelto H-M, Nilsson S, Gustafsson J-A. Cloning of a novel estrogen receptor expressed in rat prostate and ovary.  Proc Natl Acad Sci USA. 1996;  93 5925-5930
  • 6 Cowley S M, Parker M G. A comparison of transcriptional activation by ERa and ERb.  J Steroid Biochem Mol Biol. 1999;  69 165-175
  • 7 Hall J M, McDonnell D P. The estrogen receptor-b isoform (ERb) of the human estrogen receptor modulates ERa transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens.  Endocrinology. 1999;  140(12) 5566-5578
  • 8 McInerney E M, Weis K E, Sun J, Mosselman S, Katzenellenbogen B S. Transcriptional activation by the human estrogen receptor subtype b (ERb) studies with ERb and ERa receptor chimeras.  Endocrinology. 1998;  139(11) 4513-4522
  • 9 Kastner P, Krust A, Turcotte B et al.. Two distinct estrogen-regulated promoters generate transcripts encoding two functionally different human progesterone receptor forms A and B.  EMBO J. 1990;  9 1603-1614
  • 10 Edwards D P. Progesterone receptor structure/function and crosstalk with cellular signaling pathways. In: Henry HL, Norman AW Encyclopedia of Hormones. San Diego, CA; Academic Press 2004
  • 11 Giangrande P H, McDonnell D P. The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene.  Recent Prog Horm Res. 1999;  54 291-313
  • 12 Li X, O'Malley B W. Unfolding the action of progesterone receptor.  J Biol Chem. 2003;  278 39261-39264
  • 13 Baulieu E E. Cell membrane a target for steroid hormone.  Mol Cell Endocrinol. 1978;  12 247-254
  • 14 Benten W P, Lieberherr M, Sekeris C E, Wunderlich F. Testosterone induces Ca2 + influx via non-genomic surface receptors in activated T cells.  FEBS Lett. 1997;  407 211-214
  • 15 Pietras R J, Szego C M. Specific binding sites of estrogen at the outer surface of isolated endometrial cells.  Nature. 1977;  265 69-72
  • 16 Falkenstein E, Norman A W, Wehling M. Mannheim classification of non genomically initiated (rapid) steroid action(s).  J Clin Endocrinol Metab. 2000;  85 2071-2075
  • 17 Simoncini T, Genazzani A R. Non-genomic actions of sex steroid hormones.  Eur J Endocrinol. 2003;  148 281-292
  • 18 Bjornstrom L, Sjoberg M. Signal transducers and activator of transcription as downstream targets of nongenomic estrogen receptor actions.  Mol Endocrinol. 2002;  16(10) 2202-2214
  • 19 Duan R, Xie W, Burghardt R C, Safe S. Estrogen receptor-mediated activation of serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1.  J Biol Chem. 2001;  276 11590-11598
  • 20 Kousteni S, Bellido T, Plotkin L I et al.. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen recptors: dissociation from transcriptional activity.  Cell. 2001;  104 719-730
  • 21 Kousteni S, Chen J R, Bellido T et al.. Reversal of bone loss in mice by non-genotropic signaling of sex steroids.  Science. 2002;  298 843-846
  • 22 Pedram A, Razandi M, Aitkenhead M, Hughes C W, Levin E R. Integration of the non-genomic and genomic actions of estrogen. Membrane-initiated signaling by steroid to transcription and cell biology.  J Biol Chem. 2002;  277(52) 50768-50775
  • 23 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. 2005;  25 8273-8284
  • 24 Zhu Y, Rice C D, Pang Y, Pace M, Thomas P. Cloning, expression and characterization of a novel membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes.  Proc Natl Acad Sci USA. 2003;  100 2231-2236
  • 25 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. 2003;  100(5) 2237-2242
  • 26 Karteris E, Zervou S, Pang Y et al.. Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term.  Mol Endocrinol. 2006;  20 1519-1534
  • 27 Krietsch T, Fernandes M S, Kero J et al.. Human homologs of the putative G protein-couple membrane progestin receptors (mPRα, β, γ) localize to the endoplasmic reticulum and are not activated by progesterone.  Mol Endocrinol. 2006;  20 3146-3164
  • 28 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. 2005;  307 1625-1630
  • 29 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. 2005;  146 624-632
  • 30 Filardo E J, Quinn J A, Bland K I, Frackelton A RJ. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via transactivation of the epidermal growth factor receptor through release of HB-EGF.  Mol Endocrinol. 2000;  14 1649-1660
  • 31 Filardo E J, Quinn J A, Frackelton A RJ, Bland K I. Estrogen action via the G protein-coupled receptor, GPR30: Stimulation of adenylyl cyclase and cAMP-mediated attenuation of epidermal growth factor receptor-to-MAPK signaling axis.  Mol Endocrinol. 2002;  16 70-84
  • 32 Maggiolini M, Vivacqua A, Fasanella G et al.. The G protein-coupled receptor GPR30 mediates c-fos up-regualtion by 17β-estradiol and phytoestrogens in breast cancer cells.  J Biol Chem. 2004;  279 27008-27016
  • 33 Pedram A, Razandi M, Levin E R. Nature of functional estrogen receptors at the plasma membrane.  Mol Endocrinol. 2006;  20 1996-2009
  • 34 Ahola T M, Manninen T, Alokio N, Ylikomi T. G protein-coupled receptor 30 is critical for a progestin-induced growth inhibition in MCF-7 breast cancer cells.  Endocrinology. 2002;  143(9) 3376-3384
  • 35 Bologa C G, Revankar C M, Young S M et al.. Virtual and biomolecular screening converge on a selective agonist for GPR30.  Nat Chem Biol. 2006;  2 207-212
  • 36 Figueroa-Valverde L, Luna H, Castillo-Henkel C, Munoz-Gracia O, Morato-Cartagena T, Ceballos-Reyes G. Synthesis and evaluation of the cardiovascular effects of two, membrane impermeant macromolecular complexes of dextran-testosterone.  Steroids. 2002;  67 611-619
  • 37 Kampa M, Papakonstanti E A, Hotzoglou A, Stathopoulos E N, Stournaras C, Castanas E. The human prostate cancer cell line LNCaP bears functional membrane testosterone receptors that increase PSA secretion and modify actin cytoskeleton.  FASEB J. 2002;  16 1429-1431
  • 38 Kampa M, Nifi A P, Charalampopoulos I et al.. Opposing effects of estradiol- and testosterone-membrane binding sites on T47D breast cancer cell apoptosis.  Exp Cell Res. 2005;  307 41-51
  • 39 Armen T A, Gay C V. Simultaneous detection and functional response of testosterone and estradiol receptors in osteoblast plasma membranes.  J Cell Biochem. 2000;  79 620-627
  • 40 Guo Z, Benten W P, Krucken J, Wunderlich F. Nongenomic testosterone calcium signaling. Genotropic actions in androgen receptor-free macrophages.  J Biol Chem. 2002;  277 29600-29607
  • 41 Benten W P, Lieberherr M, Giese G et al.. Functional testosterone receptors in plasma membranes of T cells.  FASEB J. 1999;  13 123-133
  • 42 Papakonstanti E A, Marilena K, Castanas E, Stournaras C. A rapid, nongenomic, signaling pathway regulates the actin reorganization induced by activation of membrane testosterone receptors.  Mol Endocrinol. 2003;  17(5) 870-881
  • 43 Srivastava A K, Dey S B, Roy S K. Interaction of cyproterone acetate with sex hormone binding globulin of monkey plasma.  Exp Clin Endocrinol. 1983;  82 232-234
  • 44 Nakhla A M, Leonard J, Hryb D J, Rosner W. Sex hormone binding globulin receptor signal transduction proceeds via a G-protein.  Steroids. 1999;  64 213-216
  • 45 Nakhla A M, Romas N A, Rosner W. Estradiol activates the prostate androgen receptor and prostate-specific antigen secretion through the intermediacy of sex hormone-binding globulin.  J Biol Chem. 1997;  272 6838-6841
  • 46 Levin E R. Cellular functions of plasma membrane estrogen receptors.  Steroids. 2002;  67 471-475
  • 47 Pappas T C, Gametchu B, Watson C S. Membrane estrogen receptor identified by multiple labeling and impeded-ligand binding.  FASEB J. 1995;  9 404-410
  • 48 Sabeur K, Edwards D P, Meizel S. Human sperm plasma membrane progesterone receptor(s) and the acrosome reaction.  Biol Reprod. 1996;  54 993-1001
  • 49 Song R X, Barnes C J, Zhang Z, Bao Y, Kumar R, Santen R J. The role of Shc and insulin-like growth factor I receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane.  Proc Natl Acad Sci USA. 2004;  101 2076-2081
  • 50 Song R X-D, McPherson R A, Adam L et al.. Linkage of rapid estrogen action to MAPK activation of ERa-Shc association and Shc pathway activation.  Mol Endocrinol. 2002;  16 116-127
  • 51 Razandi M, Pedram A, Greene G L, Levin E R. Cell membrane and nuclear estrogen receptors drive from a single transcript: studies of ERa and ERb expressed in CHO cells.  Mol Endocrinol. 1999;  13 307-319
  • 52 Razandi M, Oh P, Pedram A, Schnitzer J, Levin E R. ERs associates with and regulate the production of caveolin: implications for signaling and cellular actions.  Mol Endocrinol. 2002;  16(1) 100-115
  • 53 Rai D, Frolova A, Frasor J, Carpenter A E, Katzenellenbogen B S. Distinctive actions of membrane-targeted versus nuclear localized estrogen receptors in breast cancer cells.  Mol Endocrinol. 2005;  19 1606-1617
  • 54 Razandi M, Pedram A, Merchenthaler I, Greene G L, Levin E R. Plasma membrane estrogen receptors exist and functions as dimers.  Mol Endocrinol. 2004;  18 2854-2865
  • 55 Abraham I M, Todman M G, Korach K S, Herbison A E. Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain.  Endocrinology. 2004;  145 3055-3061
  • 56 Evinger A JI, Levin E R. Requirement for estrogen receptor α membrane localization and function.  Steroids. 2005;  70 361-363
  • 57 Razandi M, Alton G, Pedram A, Ghonshani S, Webb P, Levin E R. Identification of structural determinant necessary for the localization and function of estrogen receptor a at the plasma membrane.  Mol Cell Biol. 2003;  23(5) 1633-1646
  • 58 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. 2003;  100 4807-4812
  • 59 Marquez D C, Pictras R J. Membrane-associated binding sites for estrogen contribute to growth regulation of human breast cancer cells.  Oncogene. 2001;  2001(20) 5420-5430
  • 60 Hammes S R. Steroid and oocyte maturation-a new look at an old story.  Mol Endocrinol. 2004;  18 769-775
  • 61 Maller J L. The elusive progesterone receptor in Xenopus oocytes.  Proc Natl Acad Sci USA. 2001;  98 8-10
  • 62 Bayaa M, Booth R A, Sheng Y, Liu X J. The classical progesterone receptor mediates Xenopus oocyte maturation through a nongenomic mechanism.  Proc Natl Acad Sci USA. 2000;  97 12607-12612
  • 63 Tian J, Kim S, Heilig E, Ruderman J V. Identification of XPR-1, a progesterone receptor required for Xenopus oocyte activation.  Proc Natl Acad Sci USA. 2000;  97 14358-14363
  • 64 Bagowski C P, Myers J W, Ferrell Jr J E. The classical progesterone receptor associates with p42 MAPK and is involved in phosphatidylinositol 3-kinase signaling in Xenopus oocytes.  J Biol Chem. 2001;  276(40) 37708-37714
  • 65 Lutz L B, Cole M K, Gupta K W, Kwist R J, Auchus R J, Hammes S R. 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. 2001;  98 13728-13733
  • 66 Lutz L B, Jamnonjit M, Yang W-H, Jahani D, Gill A, Hammes S R. Selective modulation of genomic and nongenomic androgen responses by androgen receptor ligands.  Mol Endocrinol. 2003;  17 1106-1116
  • 67 Gill A, Jamnonjit M, Hammes S R. Androgens promote maturation and signaling in mouse oocytes independent of transcription: a release of inhibition model for mammalian oocyte meiosis.  Mol Endocrinol. 2004;  18 97-104
  • 68 Mulholland D J, Dedhar S, Coetzee G A, Nelson C C. Interaction of nulcear receptors with the Wnt/β-catenin/Tcf axis: Wnt you like to know?.  Endocr Rev. 2005;  26 898-915
  • 69 Smart E J, Graft G A, McNiven M A et al.. Caveolins, liquid-ordered domains, and signal transduction.  Mol Cell Biol. 1999;  19 7289-7304
  • 70 Lu M L, Schneider M C, Zheng Y, Zhang X, Richie J P. Caveolin-1 interact with androgen receptor. A positive modulator of androgen receptor mediated transactivation.  J Biol Chem. 2001;  276 13442-13451
  • 71 Schlegel A, Wang C, Katzenellenbogen B S, Pestell R G, Lisanti M P. Caveolin-1 potentiates estrogen receptor alpha (ERα) signaling, caveolin-1 drives ligand-independent nuclear translocation and activation of ERα.  J Biol Chem. 1999;  274 33551-33556
  • 72 Salatino M, Beguelin W, Peters M G et al.. Progestin-induced caveolin-1 expression mediates breast cancer cell proliferation.  Oncogene. 2006;  25 7723-7739
  • 73 Lu Q, Pallas D C, Surks H K, Baur W E, Mendelsohn M E, Karas R H. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha.  Proc Natl Acad Sci USA. 2004;  101 17126-17131
  • 74 Lee H, Park D S, Razani B, Russell R G, Lisanti M P. Caveolin mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 ( - / - ) null mice show mammary epithelial cell hyperplasia.  Am J Pathol. 2002;  161 1357-1369
  • 75 Li T, Sotgia F, Vuolo M et al.. Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor α-positive status.  Am J Pathol. 2006;  168 1998-2013
  • 76 Thompson T C, Timme T L, Li L, Goltsov A. Caveolin-1, a metastasis-related gene that promote cell survival in prostate cancer.  Apoptosis. 1999;  4(4) 233-237
  • 77 Kumar R, Wang R-A, Mazumdar A et al.. A naturally occurring MTA1 variant sequesters oestrogen receptor-a in the cytoplasm.  Nature. 2002;  418 654-657
  • 78 Mazumdar A, Wang R-A, Mishra S K et al.. Transcriptional repression of estrogen receptor by metastasis-associated protein 1 corepressor.  Nat Cell Biol. 2001;  3 30-37
  • 79 Gururaj A E, Singh R R, Rayala S K et al.. MTA1, a transcriptional activator of breast cancer amplified sequence 3.  Proc Natl Acad Sci USA. 2006;  103 6670-6675
  • 80 Sato K, Nagao T, Kakumoto M et al.. Adapter protein Shc is an isoform-specific direct activator of the tyrosine kinase c-Src.  J Biol Chem. 2002;  277 29568-29576
  • 81 Cabodi S, Moro L, Baj G et al.. p130Cas interacts with estrogen receptor α and modulates non-genomic estrogen signaling in breast cancer cells.  J Cell Sci. 2004;  117 1603-1611
  • 82 Vadlamudi R K, Wang A, Mazumdar A et al.. Molecular cloning and characterization of PELP-1, a novel human coregulator of estrogen receptor α.  J Biol Chem. 2001;  276 38272-38279
  • 83 Wong C-W, McNally C, Nickbarg E, Komm B S, Cheskis B J. Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade.  Proc Natl Acad Sci USA. 2002;  99(23) 14783-14788
  • 84 Barletta F, Wong C-W, McNally B S, Komm B S, Katzenellenbogen B S, Cheskis B J. Characterization of the interactions of estrogen receptor and MNAR in the activation of c-Src.  Mol Endocrinol. 2004;  18 1096-1108
  • 85 Unni E, Sun S, Nan B et al.. Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence.  Cancer Res. 2004;  64 7156-7168
  • 86 Haas D, White S N, Lutz L B, Rasar M, Hammes S R. The modulator of nongenomic actions of estrogen receptor (MNAR) regulates transcription-independent androgen receptor-mediated signaling: Evidence that MNAR participates in G protein-regulated meiosis in Xenopus laevis oocytes.  Mol Endocrinol. 2005;  19 2035-2046
  • 87 Nakajima T, Kitazawa T, Hamada E, Hazama H, Omata M, Kurachi Y. 17β-estradiol inhibits the voltage-dependent L-type Ca2+currents in aortic smooth muscle cells.  Eur J Pharmacol. 1995;  294 625-635
  • 88 White R E, Darkow D J, Lang J L. Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism.  Circ Res. 1995;  77 936-942
  • 89 Valverde M A, Rojas P, Amigo J, Cosmelli D, Orio P, Bahamonde M I. Acute activation of Maxi-K channels (hSlo) by estradiol binding to the beta subunit.  Science. 1999;  285 1929-1931
  • 90 Mendoza C, Soler A, Tesarik J. Non-genomic steroid action: independent targeting of a plasma membrane calcium channel and a tyrosine kinase.  Biochem Biophys Res Commun. 1995;  210 518-523
  • 91 Grosse B, Kachkache M, Le Mellay V, Lieberherr M. Membrane signaling and progesterone in female and male osteoblasts: involvement of intracellular Ca2+, inositol triphosphate and diacylglycerol, but not cAMP.  J Cell Biochem. 2000;  79 334-345
  • 92 Barbagallo M, Dominguez L J, Licata G, Shan J, Bing L, Karpinski E. Vascular effects of progesterone: role of cellular calcium regulation.  Hypertension. 2001;  37 142-147
  • 93 Le Mellay V, Grosse B, Lieberherr M. Phospholipase C beta and membrane action of calcitriol and estradiol.  J Biol Chem. 1997;  272 11902-11907
  • 94 Wyckoff M H, Chambliss K L, Mineo C et al.. Plasma membrane estrogen receptors are coupled to endothlial nitric-oxide synthase through Gai.  J Biol Chem. 2001;  276 27071-27076
  • 95 Razandi M, Pedram A, Park S T, Levin E R. Proximal events in signaling by plasma membrane estrogen receptors.  J Biol Chem. 2003;  278 2701-2712
  • 96 Kurebayashi J, Okubo S, Yamamoto Y, Sonoo H. Inhibition of HER1 signaling pathway enhances antitumor effect of endocrine therapy in breast cancer.  Breast Cancer. 2004;  11 38-41
  • 97 Grazzini E, Guillon G, Mouillac B, Zingg H H. Inhibition of oxytocin receptor function by direct binding of progesterone.  Nature. 1998;  392 509-512
  • 98 Heinlein C A, Chang C. The role of androgen receptors and androgen-binding proteins in nongenomic androgen actions.  Mol Endocrinol. 2002;  16 2181-2187
  • 99 Sun Y-H, Gao X, Tang Y-J, Xu C-L, Wang L-H. Androgens induces increases intracelluar calcium via a G-protein-coupled receptor in LNCaP prostate cancer cells.  J Androl. 2006;  27 671-678
  • 100 Thomas S M, Brugge J S. Celluar functions regulated by Src family kinases.  Annu Rev Cell Dev Biol. 1997;  13 513-609
  • 101 Xu W, Doshi A, Lei M, Eck M J, Harrison S C. Crystal structures of c-Src reveal features of its autoinhibitory mechanism.  Mol Cell. 1999;  3 629-638
  • 102 Castoria G, Barone M V, Demenico M D et al.. Non-transcriptional action of estradiol and progestin triggers DNA synthesis.  EMBO J. 1999;  18 2500-2510
  • 103 Boonyaratanakornkit V, Scott M P, Ribon 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. 2001;  8 269-280
  • 104 Boonyaratanakornkit V, McGowan E J, Sherman L, Mancini M A, Cheskis B J, Edwards D P. The role of extra-nuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and cell cycle.  Mol Endocrinol. 2006(November);  30 , (Epub ahead of print)
  • 105 Lim C S, Baumann C T, Hutun H et al.. Differential localization and activity of the -A and -B forms of the human progesterone receptor using green fluorescent protein chimeras.  Mol Endocrinol. 1999;  13 366-375
  • 106 Ballare C, Uhrig M, Betchtold T 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. 2003;  23 1994-2008
  • 107 Proietti C, Salatino M, Rosemblit C et al.. Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells.  Mol Cell Biol. 2005;  25 4826-4840
  • 108 Migliaccio A, Castoria G, Di Domenico M et al.. Steroid-induced androgen receptor-oestradiol receptor-β-Src complex triggers prostate cancer cell proliferation.  EMBO J. 2000;  19 5406-5417
  • 109 Migliaccio A, Domenico M D, Castoria G et al.. Steroid receptor regulation of epidermal growth factor signaling through Src in breast and prostate cancer cells: steroid antagonist action.  Cancer Res. 2005;  65 10585-10593
  • 110 Migliaccio A, Domenico M D, Castoria G et al.. Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells.  EMBO. 1996;  15 1292-1300
  • 111 Endoh H, Sasaki H, Maruyama K et al.. Rapid activation of MAP kinase by estrogenin the bone cell line.  Biochem Biophys Res Commun. 1997;  235 99-102
  • 112 Bi R, Broutman G, Foy M R, Thompson R F, Baudry M. The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus.  Proc Natl Acad Sci USA. 2000;  97 3602-3607
  • 113 Di Domenico M, Castoria G, Bilancio A, Migliaccio A, Auricchio F. Estradiol activation of human colon carcinoma-derived Caco-2 cell growth.  Cancer Res. 1996;  56 4516-4521
  • 114 Nguyen T-V, Yao M, Pike C J. Androgen activates mitogen-activated protein kinase signaling: role in neuroprotection.  J Neurochem. 2005;  94 1639-1651
  • 115 Razandi M, Pedram A, Levin E R. Estrogen signals to the preservation of endothelial cell from and function.  J Biol Chem. 2000;  275 38540-38546
  • 116 Seval Y, Cakmak H, Kayisli U A, Arici A. Estrogen-mediate regulation of p38 mitogen-activated protein kinase in human endometrium.  J Clin Endocrinol Metab. 2006;  91 2349-2357
  • 117 Razandi M, Pedram A, Levin E R. Plasma membrane estrogen receptor signal to antiapoptosis in breast cancer.  Mol Endocrinol. 2000;  14 1434-1447
  • 118 Funaki M, Katagiri H, Inukai K, Kikuchi M, Asano T. Structure and function of phosphatidylinositol-3,4 kinase.  Cell Signal. 2000;  12 135-142
  • 119 Simoncini T, Hafezi-Moghadam A, Brazil D P, Ley K, Chin W W, Liao J K. Interaction of oestrogen receptor with the regulatory subunit of phosphotidylinositol-3-OH kinase.  Nature. 2000;  407 538-541
  • 120 Castoria G, Migliaccio A, Bilancio A et al.. PI3 kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells.  EMBO J. 2001;  20 6050-6059
  • 121 Haynes M P, Li L, Sinha D et al.. Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen.  J Biol Chem. 2003;  278 2118-2123
  • 122 Sun M, Yang L, Feldman R I et al.. Activation of phosphatidylinositol 3-kinase/Akt pathway by androgen through interaction of p85α, androgen receptor and Src.  J Biol Chem. 2003;  278 42992-43000
  • 123 Duan R, Xie W, Li X, McDougal A, Safe S. Estrogen regulation of c-fos gene expression through phosphotidylinositol-3-kinase dependent activation of serum response factor in MCF-7 breast cancer cells.  Biochem Biophys Res Commun. 2002;  294 384-394
  • 124 Chen Y H, Lee M J, Chang H H, Hung P F, Kao Y H. 17 beta-estradiol stimulates resistin gene expression in 3T3-L1 adipocytes via the estrogen receptor, extracellularly regulated kinase, and CCAAT/enhancer binding protein-alpha pathways.  Endocrinology. 2006;  147 4496-4504
  • 125 Faivre E, Skildum A, Pierson-Mullany L, Lange C A. Integration of progesterone receptor mediated rapid signaling and nuclear actions in breast cancer cell models: role of mitogen-activated protein kinases and cell cycle regulators.  Steroids. 2005;  70 418-426
  • 126 Faivre E J, Lange C A. Progesterone receptor upregulate Wnt-1 to induce EGFR-transactivation of c-Src dependent sustained activation of Erk 1/2 MAP kinase in breast cancer cells.  Mol Cell Biol. 2006;  27 466-480
  • 127 Saitoh M, Ohmichi M, Takahashi H et al.. Medroxyprogesterone acetate induces cell proliferation through up-regulation of cyclin D1 expression via phosphatidylinositol 3-kinase/Akt/nuclear factor-kappaB cascade in human breast cancer cells.  Endocrinology. 2005;  146 4917-4925
  • 128 Shah Y M, Rowan B G. The Src kinase pathway promotes tamoxifen agonist action in Ishikawa endometrial cells through phosphorylation-dependent stabilization of estrogen receptor (alpha) promoter interaction and elevated steroid receptor coactivator 1 activity.  Mol Endocrinol. 2005;  19 732-748
  • 129 Dutertre M, Smith C L. Ligand-independent interactions of p160/steroid receptor coactivators and CREB-binding protein (CBP) with estrogen receptor-alpha: regulation by phosphorylation sites in the A/B region depends on other receptor domains.  Mol Endocrinol. 2003;  17 1296-1314
  • 130 Wu R C, Qin J, Yi P et al.. Selective phosphorylations of the SRC-3/AIBI coactivator integrate genomic responses to multiple cellular signaling pathways.  Mol Cell. 2004;  15 937-949
  • 131 Harrington W R, Kim S H, Funk C C et al.. Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action.  Mol Endocrinol. 2006;  20 491-502

Viroj BoonyaratanakornkitPh.D. 

Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza

MS-130, Houston, TX 77030