Development - Ligand-independent activation of ESR1 and ESR2

Click on a target from the pathway image to view related information. Zoom     View Legend

photo_map
 


Human PrimePCR Selections
photo_fpc
ESR1 and ESR2 Activation H96

Predesigned 96-well panel for use with SYBR® Green

 

List Price:  $394.00

 

Your Price : Log In

photo_fpc
ESR1 and ESR2 Activation H384

Predesigned 384-well panel for use with SYBR® Green

 

List Price:  $523.00

 

Your Price : Log In

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) [8], [12].

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) [8], [13], [14], [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 [1], [17].

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) [14], [18], [21]. 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].

References:

  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 (New York, N.Y.) 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, deoxyribonucleic acid, and coregulators associated with alterations in estrogen and tamoxifen activity. Molecular endocrinology (Baltimore, Md.) 2006 Dec;20(12):3120-32
  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

Target Details

Click on a target from the pathway image to view related information.

[ Close ]
Click here to print
[ Close ]
Click here to print
 

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined

undefined

undefined

My PrimePCR Hot List stores your saved PrimePCR products and configurations

undefined