Receptor Mechanisms Mediating Non-Genomic Actions of Sex Steroids

 

 Buy Article Permissions and Reprints

ABSTRACT

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.

REFERENCES

• 1 Mangelsdorf D J, Tummel C, Beato M et al.. The nuclear receptor superfamily: the second decade.  Cell. 1995;  83 835-839
  CrossrefPubMedGoogle Scholar
• 2 Tsai M, O'Malley B. Molecular mechanisms of action of steroid/thyroid receptor superfamily members.  Annu Rev Biochem. 1994;  63 451-486
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  Google Scholar
• 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
  PubMedGoogle Scholar
• 12 Li X, O'Malley B W. Unfolding the action of progesterone receptor.  J Biol Chem. 2003;  278 39261-39264
  CrossrefPubMedGoogle Scholar
• 13 Baulieu E E. Cell membrane a target for steroid hormone.  Mol Cell Endocrinol. 1978;  12 247-254
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 17 Simoncini T, Genazzani A R. Non-genomic actions of sex steroid hormones.  Eur J Endocrinol. 2003;  148 281-292
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 33 Pedram A, Razandi M, Levin E R. Nature of functional estrogen receptors at the plasma membrane.  Mol Endocrinol. 2006;  20 1996-2009
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 46 Levin E R. Cellular functions of plasma membrane estrogen receptors.  Steroids. 2002;  67 471-475
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 56 Evinger A JI, Levin E R. Requirement for estrogen receptor α membrane localization and function.  Steroids. 2005;  70 361-363
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 60 Hammes S R. Steroid and oocyte maturation-a new look at an old story.  Mol Endocrinol. 2004;  18 769-775
  CrossrefPubMedGoogle Scholar
• 61 Maller J L. The elusive progesterone receptor in Xenopus oocytes.  Proc Natl Acad Sci USA. 2001;  98 8-10
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 100 Thomas S M, Brugge J S. Celluar functions regulated by Src family kinases.  Annu Rev Cell Dev Biol. 1997;  13 513-609
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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)
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 117 Razandi M, Pedram A, Levin E R. Plasma membrane estrogen receptor signal to antiapoptosis in breast cancer.  Mol Endocrinol. 2000;  14 1434-1447
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar

Viroj BoonyaratanakornkitPh.D. 

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

MS-130, Houston, TX 77030

Email: virojb@bcm.tmc.edu