Development - Membrane-bound ESR1: interaction with growth factors signaling

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ESR1 (membrane): involvement in growth factors signaling

Estrogen receptor alpha (ESR1) can occur in the cell in 2 forms: in the nucleus (ESR1 (nuclear)) and in the plasma membrane (ESR1 (membrane)) [1], [2]. ESR1 (membrane) is involved with transduction of the nongenomic effects of estrogen. ESR1 (membrane) can co-opt with Insulin-like growth factor-1 receptor (IGF-1 receptor) and v-Erb-b2 erythroblastic leukemia viral oncogene homolog 2 and 3 (ErbB2 and ErbB2) signaling pathways and uses their downstream common adapter proteins to transduce signals, leading to the activation of Mitogen-activated protein kinase 1 and 3 (ERK1/2) and/or RAC-alpha serine/threonine kinase (AKT) cascades [3], [4], [5].

Estradiol is the physiological agonist of ESR1 (membrane). Estradiol as classical steroid hormone diffuses through plasma membrane and induces two rapid processes: 1) binding of ESR1 (membrane) to the adapter molecule Src homology 2 domain-containing transforming protein 1 (Shc); 2) translocation of ESR1 (membrane) to the cell membrane [6]. Shc binds to docking sites of the IGF-1 receptor. Formation of the ESR1 (membrane)/ Shc/ IGF-1 receptor complex leads to activation of IGF-1 receptor by phosphorylation catalyzed, possibly, by the v-Src sarcoma viral oncogene homolog (c-Src) [5], [7], [8]. Proline, glutamic acid and leucine rich protein 1 (PELP1) directly binds to both ESR1 (membrane) and c-Src. Coordinate interactions between PELP1, ESR1 (membrane) and c-Src lead to c-Src activation [5], [9].

The adaptor protein Breast cancer anti-estrogen resistance 1 (p130Cas) also participates in ESR1 (membrane)-mediated activation of c-Src [4], [10].

When ERK1/2 cascade is stimulated by ESR1 (membrane), IGF-1 receptor activates Shc by phosphorylation [8], [11], [12]. In addition, c-Src may also phosphorylate Shc [13]. Shc and Growth factor receptor-bound protein 2 (Grb2) recruit exchange factor Son of sevenless homolog 1 (SOS), and form a protein complex consisting of Shc / Grb2 / SOS. Activated SOS stimulates small GTPase Harvey rat sarcoma virus oncogene 1 (H-RAS) by converting it from an inactive GDP-bounding state to the active GTP-bounding state. The activated H-RAS presumably stimulates v-Raf murine sarcoma viral oncogene homolog B1 (B-Raf)/ MAP kinase kinase 1 and 2 (MEK1 and MEK2)/ ERK1/2 cascade [12], [14], [15].

ERK1/2 can phosphorylate member of ETS oncogene family Elk-1, and thus stimulate transcription of cellular oncogene c-Fos [16], [17]. In addition, ERK1/2 can activate cAMP responsive element binding protein 1 (CREB1) by direct phosphoryling it and/or via activation of Ribosomal protein S6 kinase, 90kDa, polypeptide 1 (p90RSK1) [18]. It is possible, that ESR1 (membrane)-dependent stimulation of Cyclin D1 transcription [10] may be activated by CREB1 [19] and/or c-Fos [20].

Another fundamental player for the integration of steroid and growth factor signaling may be the Phosphoinositide-3-kinase (PI3K)/ RAC-alpha serine/threonine kinase (AKT). It is shown, that ESR1 (membrane) may participate in IGF-1 receptor- [21], [22], [23] and ErbB2/ErbB3-dependent [3] PI3K activation. Regulatory subunit of the PI3K (PI3K reg class IA) can be activated by IGF-1 receptor via Insulin receptor substrate 1 (IRS-1) [22]. PI3K reg class IA also can be directly activated by ESR1 (membrane) [24] and ErbB3 [3].

PI3K stimulates the conversion of PI(4,5)P2 to phosphatidylinositol (3,4,5) trisphosphate (PI(3,4,5)P3). PI(3,4,5)P3 binds to the pleckstrin-homology domain of AKT, recruits AKT to the plasma membrane, and exposes AKT to phosphorylation at by 3-phosphoinositide-dependent protein kinase 1 (PDK) [25], [26].

IGF-1 receptor/ ESR1 (membrane)-stimulated AKT inhibits Glycogen synthase kinase 3 (GSK3 alpha/beta), thus activating proliferation via Cyclin D1 [22]. ESR1 (membrane)/ ErbB2/ErbB3-dependent AKT induction leads to activation of transfactors ESR1 (nuclear) [3].

In addition, stimulation of the ESR1 (membrane) results in rapid activation of the endothelial nitric oxide sythase (eNOS) and subsequent NO release through the PI3K/ AKT-dependent pathway [27].

It is known that p130Cas/ c-Src/ PI3K reg class IA complex participates in ESR1 (membrane)-induced ERK activation, but the exact pathway is unknown. It is suggested that c-Src/ Shc/ H-Ras/ MEK/ ERK and/or PI3K/ PDK/ MEK/ ERK pathway maybe involved in the process. [4], [10].

Signal transduction via the ESR1 (membrane) has increasingly been found to be important for the cell biological effects of estrogen, including the antiapoptotic effect, proliferation and regulation of the cell cycle (S-phase entry) [28], [29], [30].

References:

  1. Moggs JG, Orphanides G
    Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO reports 2001 Sep;2(9):775-81
  2. Evinger AJ 3rd, Levin ER
    Requirements for estrogen receptor alpha membrane localization and function. Steroids 2005 May-Jun;70(5-7):361-3
  3. Stoica GE, Franke TF, Moroni M, Mueller S, Morgan E, Iann MC, Winder AD, Reiter R, Wellstein A, Martin MB, Stoica A
    Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene 2003 Sep 11;22(39):7998-8011
  4. Shupnik MA
    Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene 2004 Oct 18;23(48):7979-89
  5. Song RX, Santen RJ
    Membrane initiated estrogen signaling in breast cancer. Biology of reproduction 2006 Jul;75(1):9-16
  6. Prossnitz ER, Arterburn JB, Sklar LA
    GPR30: A G protein-coupled receptor for estrogen. Molecular and cellular endocrinology 2007 Feb;265-266:138-42
  7. Chieffi P, Kisslinger A, Sinisi AA, Abbondanza C, Tramontano D
    17beta-estradiol-induced activation of ERK1/2 through endogenous androgen receptor-estradiol receptor alpha-Src complex in human prostate cells. International journal of oncology 2003 Sep;23(3):797-801
  8. Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R, Santen RJ
    The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane. Proceedings of the National Academy of Sciences of the United States of America 2004 Feb 17;101(7):2076-81
  9. Barletta F, Wong CW, McNally C, Komm BS, Katzenellenbogen B, Cheskis BJ
    Characterization of the interactions of estrogen receptor and MNAR in the activation of cSrc. Molecular endocrinology (Baltimore, Md.) 2004 May;18(5):1096-108
  10. Cabodi S, Moro L, Baj G, Smeriglio M, Di Stefano P, Gippone S, Surico N, Silengo L, Turco E, Tarone G, Defilippi P
    p130Cas interacts with estrogen receptor alpha and modulates non-genomic estrogen signaling in breast cancer cells. Journal of cell science 2004 Mar 15;117(Pt 8):1603-11
  11. Kahlert S, Nuedling S, van Eickels M, Vetter H, Meyer R, Grohe C
    Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway. The Journal of biological chemistry 2000 Jun 16;275(24):18447-53
  12. Zhang Z, Kumar R, Santen RJ, Song RX
    The role of adapter protein Shc in estrogen non-genomic action. Steroids 2004 Aug;69(8-9):523-9
  13. Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E, Auricchio F
    Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. The EMBO journal 1996 Mar 15;15(6):1292-300
  14. Singh M, Sétáló G Jr, Guan X, Warren M, Toran-Allerand CD
    Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. The Journal of neuroscience : the official journal of the Society for Neuroscience 1999 Feb 15;19(4):1179-88
  15. Singh M, Sétáló G Jr, Guan X, Frail DE, Toran-Allerand CD
    Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-alpha knock-out mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 2000 Mar 1;20(5):1694-700
  16. Duan R, Xie W, Burghardt RC, Safe S
    Estrogen receptor-mediated activation of the serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1. The Journal of biological chemistry 2001 Apr 13;276(15):11590-8
  17. Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R, Santen RJ
    Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation. Molecular endocrinology (Baltimore, Md.) 2002 Jan;16(1):116-27
  18. Wade CB, Dorsa DM
    Estrogen activation of cyclic adenosine 5'-monophosphate response element-mediated transcription requires the extracellularly regulated kinase/mitogen-activated protein kinase pathway. Endocrinology 2003 Mar;144(3):832-8
  19. Boulon S, Dantonel JC, Binet V, Vié A, Blanchard JM, Hipskind RA, Philips A
    Oct-1 potentiates CREB-driven cyclin D1 promoter activation via a phospho-CREB- and CREB binding protein-independent mechanism. Molecular and cellular biology 2002 Nov;22(22):7769-79
  20. Brown JR, Nigh E, Lee RJ, Ye H, Thompson MA, Saudou F, Pestell RG, Greenberg ME
    Fos family members induce cell cycle entry by activating cyclin D1. Molecular and cellular biology 1998 Sep;18(9):5609-19
  21. Mendez P, Azcoitia I, Garcia-Segura LM
    Estrogen receptor alpha forms estrogen-dependent multimolecular complexes with insulin-like growth factor receptor and phosphatidylinositol 3-kinase in the adult rat brain. Brain research. Molecular brain research 2003 Apr 10;112(1-2):170-6
  22. Surmacz E, Bartucci M
    Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer. Journal of experimental & clinical cancer research : CR 2004 Sep;23(3):385-94
  23. Zhang S, Li X, Burghardt R, Smith R 3rd, Safe SH
    Role of estrogen receptor (ER) alpha in insulin-like growth factor (IGF)-I-induced responses in MCF-7 breast cancer cells. Journal of molecular endocrinology 2005 Dec;35(3):433-47
  24. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK
    Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000 Sep 28;407(6803):538-41
  25. Shiojima I, Walsh K
    Role of Akt signaling in vascular homeostasis and angiogenesis. Circulation research 2002 Jun 28;90(12):1243-50
  26. Aquila S, Sisci D, Gentile M, Middea E, Catalano S, Carpino A, Rago V, Andò S
    Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa: evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway. The Journal of clinical endocrinology and metabolism 2004 Mar;89(3):1443-51
  27. Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M, Sessa WC, Bender JR
    Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circulation research 2000 Oct 13;87(8):677-82
  28. Castoria G, Barone MV, Di Domenico M, Bilancio A, Ametrano D, Migliaccio A, Auricchio F
    Non-transcriptional action of oestradiol and progestin triggers DNA synthesis. The EMBO journal 1999 May 4;18(9):2500-10
  29. Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC
    Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001 Mar 9;104(5):719-30
  30. Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco A, Lombardi M, Fiorentino R, Varricchio L, Barone MV, Auricchio F
    PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. The EMBO journal 2001 Nov 1;20(21):6050-9

  1. Moggs JG, Orphanides G
    Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO reports 2001 Sep;2(9):775-81
  2. Evinger AJ 3rd, Levin ER
    Requirements for estrogen receptor alpha membrane localization and function. Steroids 2005 May-Jun;70(5-7):361-3
  3. Stoica GE, Franke TF, Moroni M, Mueller S, Morgan E, Iann MC, Winder AD, Reiter R, Wellstein A, Martin MB, Stoica A
    Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene 2003 Sep 11;22(39):7998-8011
  4. Shupnik MA
    Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene 2004 Oct 18;23(48):7979-89
  5. Song RX, Santen RJ
    Membrane initiated estrogen signaling in breast cancer. Biology of reproduction 2006 Jul;75(1):9-16
  6. Prossnitz ER, Arterburn JB, Sklar LA
    GPR30: A G protein-coupled receptor for estrogen. Molecular and cellular endocrinology 2007 Feb;265-266:138-42
  7. Chieffi P, Kisslinger A, Sinisi AA, Abbondanza C, Tramontano D
    17beta-estradiol-induced activation of ERK1/2 through endogenous androgen receptor-estradiol receptor alpha-Src complex in human prostate cells. International journal of oncology 2003 Sep;23(3):797-801
  8. Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R, Santen RJ
    The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane. Proceedings of the National Academy of Sciences of the United States of America 2004 Feb 17;101(7):2076-81
  9. Barletta F, Wong CW, McNally C, Komm BS, Katzenellenbogen B, Cheskis BJ
    Characterization of the interactions of estrogen receptor and MNAR in the activation of cSrc. Molecular endocrinology (Baltimore, Md.) 2004 May;18(5):1096-108
  10. Cabodi S, Moro L, Baj G, Smeriglio M, Di Stefano P, Gippone S, Surico N, Silengo L, Turco E, Tarone G, Defilippi P
    p130Cas interacts with estrogen receptor alpha and modulates non-genomic estrogen signaling in breast cancer cells. Journal of cell science 2004 Mar 15;117(Pt 8):1603-11
  11. Kahlert S, Nuedling S, van Eickels M, Vetter H, Meyer R, Grohe C
    Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway. The Journal of biological chemistry 2000 Jun 16;275(24):18447-53
  12. Zhang Z, Kumar R, Santen RJ, Song RX
    The role of adapter protein Shc in estrogen non-genomic action. Steroids 2004 Aug;69(8-9):523-9
  13. Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E, Auricchio F
    Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. The EMBO journal 1996 Mar 15;15(6):1292-300
  14. Singh M, Sétáló G Jr, Guan X, Warren M, Toran-Allerand CD
    Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. The Journal of neuroscience : the official journal of the Society for Neuroscience 1999 Feb 15;19(4):1179-88
  15. Singh M, Sétáló G Jr, Guan X, Frail DE, Toran-Allerand CD
    Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-alpha knock-out mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 2000 Mar 1;20(5):1694-700
  16. Duan R, Xie W, Burghardt RC, Safe S
    Estrogen receptor-mediated activation of the serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1. The Journal of biological chemistry 2001 Apr 13;276(15):11590-8
  17. Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R, Santen RJ
    Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation. Molecular endocrinology (Baltimore, Md.) 2002 Jan;16(1):116-27
  18. Wade CB, Dorsa DM
    Estrogen activation of cyclic adenosine 5'-monophosphate response element-mediated transcription requires the extracellularly regulated kinase/mitogen-activated protein kinase pathway. Endocrinology 2003 Mar;144(3):832-8
  19. Boulon S, Dantonel JC, Binet V, Vié A, Blanchard JM, Hipskind RA, Philips A
    Oct-1 potentiates CREB-driven cyclin D1 promoter activation via a phospho-CREB- and CREB binding protein-independent mechanism. Molecular and cellular biology 2002 Nov;22(22):7769-79
  20. Brown JR, Nigh E, Lee RJ, Ye H, Thompson MA, Saudou F, Pestell RG, Greenberg ME
    Fos family members induce cell cycle entry by activating cyclin D1. Molecular and cellular biology 1998 Sep;18(9):5609-19
  21. Mendez P, Azcoitia I, Garcia-Segura LM
    Estrogen receptor alpha forms estrogen-dependent multimolecular complexes with insulin-like growth factor receptor and phosphatidylinositol 3-kinase in the adult rat brain. Brain research. Molecular brain research 2003 Apr 10;112(1-2):170-6
  22. Surmacz E, Bartucci M
    Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer. Journal of experimental & clinical cancer research : CR 2004 Sep;23(3):385-94
  23. Zhang S, Li X, Burghardt R, Smith R 3rd, Safe SH
    Role of estrogen receptor (ER) alpha in insulin-like growth factor (IGF)-I-induced responses in MCF-7 breast cancer cells. Journal of molecular endocrinology 2005 Dec;35(3):433-47
  24. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK
    Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000 Sep 28;407(6803):538-41
  25. Shiojima I, Walsh K
    Role of Akt signaling in vascular homeostasis and angiogenesis. Circulation research 2002 Jun 28;90(12):1243-50
  26. Aquila S, Sisci D, Gentile M, Middea E, Catalano S, Carpino A, Rago V, Andò S
    Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa: evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway. The Journal of clinical endocrinology and metabolism 2004 Mar;89(3):1443-51
  27. Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M, Sessa WC, Bender JR
    Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circulation research 2000 Oct 13;87(8):677-82
  28. Castoria G, Barone MV, Di Domenico M, Bilancio A, Ametrano D, Migliaccio A, Auricchio F
    Non-transcriptional action of oestradiol and progestin triggers DNA synthesis. The EMBO journal 1999 May 4;18(9):2500-10
  29. Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC
    Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001 Mar 9;104(5):719-30
  30. Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco A, Lombardi M, Fiorentino R, Varricchio L, Barone MV, Auricchio F
    PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. The EMBO journal 2001 Nov 1;20(21):6050-9

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