Pathway maps

Development_Ligand-independent activation of ESR1 and ESR2
Development_Ligand-independent activation of ESR1 and ESR2

Object List (links open in MetaCore):

MEK2(MAP2K2), NCOA3, c-Raf-1, AKT(PKB), ERK2 (MAPK1), EGFR, PI3K cat class IA, CBP, ErbB3, PIP3, ErbB2, Shc, ERK1 (MAPK3), ESR1 (nuclear), ATP, PDK (PDPK1), NCOA2 , PKA-cat ,, NCOA1 , Caveolin-1, Galpha(s)-specific GPCRs, H-Ras, IGF-1 receptor,, IGF-1, EGF, p300, PKA-reg , PI3K reg class IA, GRB2, p90RSK1, SOS, PIP2, ESR2, MEK1(MAP2K1), IRS-1, Cyclin D1, Neuregulin 1, G-protein alpha-s, ERK1/2, Adenylate cyclase, cAMP, TFF1


Ligand-independent activation of ESR1 and ESR2

In addition to the conventional hormone-dependent regulation of activity of Estrogen receptor alpha and beta ( ESR1(nuclear) and ESR2 respectively), there is a cross-talk between signal transduction pathways and estrogen receptors [1]. Epidermal growth factor ( EGF ), Insulin-like growth factor-1 ( IGF-1 ), stimulators of cAMP-dependent signaling pathway regulate transcriptional activity of the ESR1(nuclear) and ESR2 in the absence of ligand [2], [3], [4]. Regulators of ESR1 (nuclear) and ESR2 transcriptional activity activate multiple signaling pathways.

EGF and IGF-1 activate ESR1(nuclear) by binding to the corresponding receptors (Epidermal growth factor receptor ( EGFR ) and Insulin-like growth factor 1 receptor ( IGF-1 receptor ) respectively) followed by stimulation of mitogen-activated protein kinases (MAPK) cascade - signaling pathway. ESR2 is activated only by EGF signaling [5], [6]. The adaptors Src homology 2 domain-containing transforming protein 1 ( Shc ) and Growth factor receptor-bound protein 2 ( Grb2 ) recruit exchange factor Son of sevenless homolog ( SOS ), forming a protein complex Shc/ Grb2/ SOS. Activated SOS stimulates small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) by its conversion from the inactive GDP-bounding state to the active GTP-bounding state. The activated H-RAS stimulates v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1) MEK2(MAP2K2) )/ Mitogen activated protein kinases 1-3 ( ERK1/2 ) cascade, which leads to higher transcriptional activity of ESR1 (nuclear) and ESR2. ERK1/2 can activate ESR1 (nuclear) and ESR2 by direct phosphorylation [5], [7], [8] or via phosphorylation of coregulatory proteins such as Nuclear receptor co-activators 1, 2 and 3 ( NCOA1 (SRC1), NCOA2 (GRIP1/TIF2) and NCOA3 (pCIP/SRC3), respectively) [9], [10], [11].

EGF also activates Ribosomal protein S6 kinase, 90kDa, polypeptide 1 ( p90RSK1 ) (most probably through MAP kinases pathway), which phosphorylates and enhances transcriptional activity of ESR1 (nuclear) [12], [8] .

The second pathway which stimulates exclusively ESR1 (nuclear) by EGF and IGF-1 includes activation Phosphoinositide-3-kinase ( PI3K )/ V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ) cascade. EGFR (directly) and IGF-1 receptor (via Insulin receptor substrate 1 ( IRS-1 )) activate PI3K which converts phosphatidylinositol 4,5-biphosphate ( PtdIns(4,5)P2 ) to phosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ). PtdIns(3,4,5)P3 associates with the inner face of the plasma membrane promoting the recruitment and activation of the AKT(PKB). Both PI3K and AKT(PKB) phosphorylate ESR1 (nuclear) [13], [14], [8], [15].

Neuregulin-1 also activates ESR1 (nuclear) in a ligand-independent manner via PI3K/ AKT(PKB) pathway. Neuregulin-1 interacts with an v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog of ( ErbB2 )/ v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 ( ErbB3 ) heterodimers; activated ErbB3 recruits and activates PI3K and, consequently, AKT(PKB) and ESR1 (nuclear) phosphorylated by AKT(PKB) [16].

Stimulation of cAMP/ Protein kinase, cAMP-dependent ( PKA ) signaling likely proceeds via G-protein alpha-s which activates Adenylate cyclase. Activation of PKA by cAMP is the third ligand-independent signaling pathway which stimulates ESR1 (nuclear) [2], [8], [15].

During stimulation of cAMP signaling pathway, coactivator Cyclin D1 enhances transcriptional activity of ESR1 (nuclear) in a ligand-independent manner [17], [1].

Co-regulatory proteins NCOA1 (SRC1), NCOA2 (GRIP1/TIF2) and NCOA3 (pCIP/SRC3) in response to growth factors overall ligand-independent ESR activation may be due to more efficient recruitment of coactivators to the ESR1 (nuclear) and ESR2 [10], [18], [19]. Phosphorylation of ESR1 (nuclear) increases affinity of coactivators such as NCOA3 [15]. ESR1 (nuclear) -coactivator complex then recruits integrator proteins such as CREB binding protein ( CBP ) and E1A binding protein p300 ( p300 ), which by DNA looping brings the receptor-containing regulatory region of the gene into proximity with the actual transcriptional start site [10], [18].

Caveolin 1, caveolae protein, 22kDa ( Caveolin-1 ) is yet another co-activator of ESR1 (nuclear) in a ligand-independent manner, which drives ERK -independent phosphorylation and activation of AF-1 domain [20].

Ligand-independent transcriptional activation of ERS1 (nuclear) and ESR2 pathways results in transcription of Trefoil-factor protein 1 ( TFF1 ) [21], [14], [18]. TFF1 display a great number of physiological actions [22], [23], [24]. Its role in ligand-independent ESR activation is not yet resolved. ERS1 (nuclear) and ESR2 inhibit cell migration and invasion and ESR2 inhibits cell proliferation in a ligand-independent manner [25], [26].


  1. Moggs JG, Orphanides G
    Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO reports 2001 Sep;2(9):775-81
  2. El-Tanani MK, Green CD
    Two separate mechanisms for ligand-independent activation of the estrogen receptor. Molecular endocrinology (Baltimore, Md.) 1997 Jun;11(7):928-37
  3. Weigel NL, Zhang Y
    Ligand-independent activation of steroid hormone receptors. Journal of molecular medicine (Berlin, Germany) 1998 Jun;76(7):469-79
  4. Driggers PH, Segars JH
    Estrogen action and cytoplasmic signaling pathways. Part II: the role of growth factors and phosphorylation in estrogen signaling. Trends in endocrinology and metabolism: TEM 2002 Dec;13(10):422-7
  5. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P
    Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 1995 Dec 1;270(5241):1491-4
  6. Bunone G, Briand PA, Miksicek RJ, Picard D
    Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. The EMBO journal 1996 May 1;15(9):2174-83
  7. Tremblay A, Tremblay GB, Labrie F, Giguere V
    Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1. Molecular cell 1999 Apr;3(4):513-9
  8. Lannigan DA
    Estrogen receptor phosphorylation. Steroids 2003 Jan;68(1):1-9
  9. Rowan BG, Weigel NL, O'Malley BW
    Phosphorylation of steroid receptor coactivator-1. Identification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway. The Journal of biological chemistry 2000 Feb 11;275(6):4475-83
  10. Font de Mora J, Brown M
    AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Molecular and cellular biology 2000 Jul;20(14):5041-7
  11. Lopez GN, Turck CW, Schaufele F, Stallcup MR, Kushner PJ
    Growth factors signal to steroid receptors through mitogen-activated protein kinase regulation of p160 coactivator activity. The Journal of biological chemistry 2001 Jun 22;276(25):22177-82
  12. Joel PB, Smith J, Sturgill TW, Fisher TL, Blenis J, Lannigan DA
    pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Molecular and cellular biology 1998 Apr;18(4):1978-84
  13. Martin MB, Franke TF, Stoica GE, Chambon P, Katzenellenbogen BS, Stoica BA, McLemore MS, Olivo SE, Stoica A
    A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. Endocrinology 2000 Dec;141(12):4503-11
  14. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H
    Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. The Journal of biological chemistry 2001 Mar 30;276(13):9817-24
  15. Likhite VS, Stossi F, Kim K, Katzenellenbogen BS, Katzenellenbogen JA
    Kinase-Specific Phosphorylation of the Estrogen Receptor Changes Receptor Interactions with Ligand, DNA, and Coregulators Associated with Alterations in Estrogen and Tamoxifen Activity. Molecular endocrinology (Baltimore, Md.) 2006 Aug 31;
  16. Stoica GE, Franke TF, Wellstein A, Morgan E, Czubayko F, List HJ, Reiter R, Martin MB, Stoica A
    Heregulin-beta1 regulates the estrogen receptor-alpha gene expression and activity via the ErbB2/PI 3-K/Akt pathway. Oncogene 2003 Apr 10;22(14):2073-87
  17. Lamb J, Ladha MH, McMahon C, Sutherland RL, Ewen ME
    Regulation of the functional interaction between cyclin D1 and the estrogen receptor. Molecular and cellular biology 2000 Dec;20(23):8667-75
  18. Dutertre M, Smith CL
    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. Molecular endocrinology (Baltimore, Md.) 2003 Jul;17(7):1296-314
  19. Klinge CM, Jernigan SC, Mattingly KA, Risinger KE, Zhang J
    Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors. Journal of molecular endocrinology 2004 Oct;33(2):387-410
  20. Schlegel A, Wang C, Pestell RG, Lisanti MP
    Ligand-independent activation of oestrogen receptor alpha by caveolin-1. The Biochemical journal 2001 Oct 1;359(Pt 1):203-10
  21. El-Tanani MK, Green CD
    Interaction between estradiol and growth factors in the regulation of specific gene expression in MCF-7 human breast cancer cells. The Journal of steroid biochemistry and molecular biology 1997 Mar;60(5-6):269-76
  22. Ribieras S, Tomasetto C, Rio MC
    The pS2/TFF1 trefoil factor, from basic research to clinical applications. Biochimica et biophysica acta 1998 Aug 19;1378(1):F61-77
  23. Bossenmeyer-Pourie C, Kannan R, Ribieras S, Wendling C, Stoll I, Thim L, Tomasetto C, Rio MC
    The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis. The Journal of cell biology 2002 May 27;157(5):761-70
  24. Baus-Loncar M, Giraud AS
    Multiple regulatory pathways for trefoil factor (TFF) genes. Cellular and molecular life sciences : CMLS 2005 Dec;62(24):2921-31
  25. Lazennec G, Bresson D, Lucas A, Chauveau C, Vignon F
    ER beta inhibits proliferation and invasion of breast cancer cells. Endocrinology 2001 Sep;142(9):4120-30
  26. Martineti V, Picariello L, Tognarini I, Carbonell Sala S, Gozzini A, Azzari C, Mavilia C, Tanini A, Falchetti A, Fiorelli G, Tonelli F, Brandi ML
    ERbeta is a potent inhibitor of cell proliferation in the HCT8 human colon cancer cell line through regulation of cell cycle components. Endocrine-related cancer 2005 Jun;12(2):455-69