Pathway Map Details

Apoptosis and survival_Anti-apoptotic action of membrane-bound ESR1

view in full size
| open in MetaCore

Object list (links open in MetaCore):

Cytochrome c, eNOS, ASK1 (MAP3K5), PDK (PDPK1), MEK1 (MAP2K1), MEK2 (MAP2K2), PKC-epsilon, ESR1 (membrane), PKC-alpha, Nitric Oxide, Bcl-2,, 17beta-Estradiol, PI3K cat class IA, c-Src, PtdIns(4,5)P2, Erk (MAPK1/3), Ca('2) cytosol, JNK (MAPK8-10), p90RSK1, Ca('2+) extracellular region, BAD, (L)-arginine, c-Raf-1, PtdIns(3,4,5)P3, PI3K reg class IA (p85), L-type Ca(II) channel, alpha 1C subunit, (S)-citrulline, Bax, Ca('2+) = Ca('2+), , Bcl-XL, AKT(PKB), CREB1, MEK4 (MAP2K4)


Anti-apoptotic action of membrane-bound ESR1

17beta-estradiol exerts an anti-apoptotic effect on a wide variety of tissues that is mediated via activation of membrane bound Estrogen receptor 1 ( ESR1(membrane) ), which activates several anti-apoptotic pathways [1], [2], [3].

Activated ESR1(membrane) binds to and activates Phosphoinositide-3-kinase ( PI3K ) [4], [5]. PI3K via Phosphatidylinositol (3,4,5) trisphosphate ( PtdIns(3,4,5)P3 ) and 3-phosphoinositide dependent protein kinase-1 ( PDK(PDPK1) ) activates V-akt murine thymoma viral oncogene homologs ( AKT(PKB) ) [6]. Upon 17beta-estradiol action, activated AKT(PKB) promotes several anti-apoptotic pathways.

Primarily, AKT(PKB) phosphorylates and activates Nitric oxide synthase 3 ( eNOS ) which catalyzes the synthesis reaction of Nitric oxide [4], [7]. Nitric oxide promotes cell survival by several mechanisms, including inhibition of mitochondrial permeability transition pore opening [8].

AKT(PKB) directly phosphorylates and activates CREB1, which regulates transcription of Bcl-2 [9], [2]. [10]. Also, AKT(PKB) phosphorylates and inhibits BAD, thus preventing its binding and inhibition of Bcl-2 and Bcl-XL [11].

As a result of 17beta-estradiol action AKT(PKB) inhibits Mitogen-activated protein kinase kinase kinase 5 ( ASK1 (MAP3K5) )/ Mitogen-activated protein kinase kinase 4 ( MEK4(MAP2K4) )/ Mitogen-activated protein kinases 8-10 ( JNK (MAPK8-10) cascade preventing inhibition of Bcl-2 and Bcl-XL [12], [13], [14].

Activation of Bcl-2 and Bcl-XL and suppression of Bax under 17beta-estradiol action prevents formation of mitochondrial permeability transition pore, release of Cytochrome C from the mitochondria into the cytoplasm, and activation of caspase cascade [11], [15].

17beta-estradiol can also activate Protein kinases C (PKC) (e.g., PKC-epsilon and/or PKC-alpha ) [16], [17]. This may be realized via PtdIns(3,4,5)P3 [18] and PDK(PDPK1) [19], [20]. PKC-epsilon and/or PKC-alpha phosphorylates voltage-dependent Calcium channel L type alpha 1C subunit ( L-type Ca(II) channel, alpha 1C subunit ) and promotes Ca('2+) transport into the cytosol [16], [21]. Intracellular Ca('2+) rise activates Ca-dependent conventional forms of PKC, possibly PKC-alpha, which activates V-src sarcoma viral oncogene homolog ( c-Src )/ V-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/ Mitogen-activated protein kinases 1 and 3 ( Erk(MAPK1/3) ) pathway [22], [23], [24]. Activated Erk(MAPK1/3) phosphorylates and activates Ribosomal protein S6 kinase 90kDa polypeptide 1 ( p90RSK1 ) [25], [26], which activates cAMP responsive element binding protein 1 ( CREB1 ), and that in turn promotes transcription of anti-apoptotic protein B-cell CLL/lymphoma 2 ( Bcl-2 ) [11], [21], [27]. PKC-epsilon activated by 17beta-estradiol action also can directly bind to BCL2-associated X protein ( Bax ) and inhibit its translocation into mitochondria [28].

ESR1 (membrane) also can directly or through G-proteins signaling activate c-Src, which further leads to Erk(MAPK1/3) and p90RSK2 (RPS6KA3) activation. Activated p90RSK1 directly inhibits BCL2-antagonist of cell death ( BAD ) [25], [26].


  1. 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
  2. Honda K, Shimohama S, Sawada H, Kihara T, Nakamizo T, Shibasaki H, Akaike A
    Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons. Journal of neuroscience research 2001 Jun 1;64(5):466-75
  3. Wang M, Crisostomo P, Wairiuko GM, Meldrum DR
    Estrogen receptor-alpha mediates acute myocardial protection in females. American journal of physiology. Heart and circulatory physiology 2006 Jun;290(6):H2204-9
  4. 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
  5. Mannella P, Brinton RD
    Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. The Journal of neuroscience : the official journal of the Society for Neuroscience 2006 Sep 13;26(37):9439-47
  6. Scheid MP, Woodgett JR
    Unravelling the activation mechanisms of protein kinase B/Akt. FEBS letters 2003 Jul 3;546(1):108-12
  7. Mendelsohn ME
    Nongenomic, ER-mediated activation of endothelial nitric oxide synthase: how does it work? What does it mean? Circulation research 2000 Nov 24;87(11):956-60
  8. Murphy E, Steenbergen C
    Cardioprotection in females: a role for nitric oxide and altered gene expression. Heart failure reviews 2007 Dec;12(3-4):293-300
  9. Du K, Montminy M
    CREB is a regulatory target for the protein kinase Akt/PKB. The Journal of biological chemistry 1998 Dec 4;273(49):32377-9
  10. Brunet A, Datta SR, Greenberg ME
    Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Current opinion in neurobiology 2001 Jun;11(3):297-305
  11. Nilsen J, Brinton RD
    Mitochondria as therapeutic targets of estrogen action in the central nervous system. Current drug targets. CNS and neurological disorders 2004 Aug;3(4):297-313
  12. Razandi M, Pedram A, Levin ER
    Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer. Molecular endocrinology (Baltimore, Md.) 2000 Sep;14(9):1434-47
  13. Eckhoff DE, Smyth CA, Eckstein C, Bilbao G, Young CJ, Thompson JA, Contreras JL
    Suppression of the c-Jun N-terminal kinase pathway by 17beta-estradiol can preserve human islet functional mass from proinflammatory cytokine-induced destruction. Surgery 2003 Aug;134(2):169-79
  14. Mabuchi S, Ohmichi M, Kimura A, Nishio Y, Arimoto-Ishida E, Yada-Hashimoto N, Tasaka K, Murata Y
    Estrogen inhibits paclitaxel-induced apoptosis via the phosphorylation of apoptosis signal-regulating kinase 1 in human ovarian cancer cell lines. Endocrinology 2004 Jan;145(1):49-58
  15. Nilsen J, Chen S, Irwin RW, Iwamoto S, Brinton RD
    Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC neuroscience 2006 Nov 3;7:74
  16. Yang L, Liu G, Zakharov SI, Morrow JP, Rybin VO, Steinberg SF, Marx SO
    Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms. The Journal of biological chemistry 2005 Jan 7;280(1):207-14
  17. Sovershaev MA, Egorina EM, Andreasen TV, Jonassen AK, Ytrehus K
    Preconditioning by 17beta-estradiol in isolated rat heart depends on PI3-K/PKB pathway, PKC, and ROS. American journal of physiology. Heart and circulatory physiology 2006 Oct;291(4):H1554-62
  18. Toker A, Meyer M, Reddy KK, Falck JR, Aneja R, Aneja S, Parra A, Burns DJ, Ballas LM, Cantley LC
    Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3. The Journal of biological chemistry 1994 Dec 23;269(51):32358-67
  19. Dutil EM, Toker A, Newton AC
    Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1). Current biology : CB 1998 Dec 17-31;8(25):1366-75
  20. Cenni V, Doppler H, Sonnenburg ED, Maraldi N, Newton AC, Toker A
    Regulation of novel protein kinase C epsilon by phosphorylation. The Biochemical journal 2002 May 1;363(Pt 3):537-45
  21. Wu TW, Wang JM, Chen S, Brinton RD
    17Beta-estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: a potential initiation mechanism for estrogen-induced neuroprotection. Neuroscience 2005;135(1):59-72
  22. Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR
    Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature 1993 Jul 15;364(6434):249-52
  23. Schonwasser DC, Marais RM, Marshall CJ, Parker PJ
    Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Molecular and cellular biology 1998 Feb;18(2):790-8
  24. Cordey M, Gundimeda U, Gopalakrishna R, Pike CJ
    Estrogen activates protein kinase C in neurons: role in neuroprotection. Journal of neurochemistry 2003 Mar;84(6):1340-8
  25. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME
    Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 1999 Nov 12;286(5443):1358-62
  26. Fernando RI, Wimalasena J
    Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras-dependent nongenomic pathways requiring signaling through ERK and Akt. Molecular biology of the cell 2004 Jul;15(7):3266-84
  27. Subramanian M, Shaha C
    Up-regulation of Bcl-2 through ERK phosphorylation is associated with human macrophage survival in an estrogen microenvironment. Journal of immunology (Baltimore, Md. : 1950) 2007 Aug 15;179(4):2330-8
  28. Lu D, Sivaprasad U, Huang J, Shankar E, Morrow S, Basu A
    Protein kinase C-epsilon protects MCF-7 cells from TNF-mediated cell death by inhibiting Bax translocation. Apoptosis : an international journal on programmed cell death 2007 Oct;12(10):1893-900