KEGG   PATHWAY: mlx04915
Entry
mlx04915                    Pathway                                
Name
Estrogen signaling pathway - Mirounga leonina (Southern elephant seal)
Description
Estrogens are steroid hormones that regulate a plethora of physiological processes in mammals, including reproduction, cardiovascular protection, bone integrity, cellular homeostasis, and behavior. Estrogen mediates its cellular actions through two signaling pathways classified as "nuclear-initiated steroid signaling" and "membrane-initiated steroid signaling". In the "nuclear" pathway, estrogen binds either ERalpha or ERbeta, which in turn translocates to the nucleus, binds DNA at ERE elements and activates the expression of ERE-dependent genes. In "membrane" pathway, Estrogen can exert its actions through a subpopulation of ER at the plasma membrane (mER) or novel G-protein coupled E2 receptors (GPER). Upon activation of these receptors various signaling pathways (i.e. Ca2+, cAMP, protein kinase cascades) are rapidly activated and ultimately influence downstream transcription factors.
Class
Organismal Systems; Endocrine system
Pathway map
mlx04915  Estrogen signaling pathway
mlx04915

Other DBs
GO: 0030520
Organism
Mirounga leonina (Southern elephant seal) [GN:mlx]
Gene
118001078  ESR1; estrogen receptor [KO:K08550]
118002390  ESR2; estrogen receptor beta isoform X1 [KO:K08551]
118014942  LOW QUALITY PROTEIN: heat shock protein HSP 90-beta-like [KO:K04079]
118001625  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
118002022  HSP90AA1; heat shock protein HSP 90-alpha [KO:K04079]
117998807  HSP90B1; endoplasmin [KO:K09487]
118001174  FKBP5; peptidyl-prolyl cis-trans isomerase FKBP5 [KO:K09571] [EC:5.2.1.8]
118025783  FKBP4; peptidyl-prolyl cis-trans isomerase FKBP4 isoform X1 [KO:K09571] [EC:5.2.1.8]
118027322  HSPA1L; heat shock 70 kDa protein 1-like isoform X1 [KO:K03283]
118013335  HSPA8; heat shock cognate 71 kDa protein [KO:K03283]
118013784  HSPA6; LOW QUALITY PROTEIN: heat shock 70 kDa protein 6 [KO:K03283]
118020648  LOW QUALITY PROTEIN: heat shock cognate 71 kDa protein-like [KO:K03283]
118007647  NCOA1; nuclear receptor coactivator 1 isoform X1 [KO:K09101] [EC:2.3.1.48]
118014907  NCOA2; nuclear receptor coactivator 2 isoform X1 [KO:K11255]
118011566  NCOA3; nuclear receptor coactivator 3 isoform X1 [KO:K11256] [EC:2.3.1.48]
118004389  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
118015130  EBAG9; receptor-binding cancer antigen expressed on SiSo cells [KO:K22455]
118008469  KRT18; keratin, type I cytoskeletal 18 [KO:K07604]
118024879  keratin, type I cuticular Ha1 isoform X1 [KO:K07604]
118024881  keratin, type I cuticular Ha3-I [KO:K07604]
118024883  keratin, type I cuticular Ha7-like [KO:K07604]
118024884  keratin, type I cuticular Ha8-like [KO:K07604]
118025072  KRT24; keratin, type I cytoskeletal 24 [KO:K07604]
118025074  KRT25; keratin, type I cytoskeletal 25 [KO:K07604]
118025075  KRT26; keratin, type I cytoskeletal 26 [KO:K07604]
118025076  keratin, type I cytoskeletal 27 [KO:K07604]
118025077  KRT28; keratin, type I cytoskeletal 28 [KO:K07604]
118025078  KRT12; keratin, type I cytoskeletal 12 [KO:K07604]
118025079  KRT20; keratin, type I cytoskeletal 20 [KO:K07604]
118025080  KRT23; keratin, type I cytoskeletal 23 isoform X1 [KO:K07604]
118025082  KRT39; keratin, type I cytoskeletal 39 [KO:K07604]
118025083  KRT40; keratin, type I cytoskeletal 40 [KO:K07604]
118025087  KRT32; keratin, type I cuticular Ha2 [KO:K07604]
118025088  keratin, type I cuticular Ha5 [KO:K07604]
118025089  KRT36; keratin, type I cuticular Ha6 [KO:K07604]
118025090  KRT15; keratin, type I cytoskeletal 15 [KO:K07604]
118025091  KRT19; keratin, type I cytoskeletal 19 [KO:K07604]
118025092  KRT14; keratin, type I cytoskeletal 14 isoform X1 [KO:K07604]
118025093  KRT16; LOW QUALITY PROTEIN: keratin, type I cytoskeletal 16 [KO:K07604]
118025094  KRT17; keratin, type I cytoskeletal 17 isoform X1 [KO:K07604]
118025095  LOW QUALITY PROTEIN: keratin, type I cytoskeletal 42-like [KO:K07604]
118025115  keratin, type I cuticular Ha1-like [KO:K07604]
118025145  KRT10; keratin, type I cytoskeletal 10 [KO:K07604]
118025152  keratin, type I cuticular Ha8-like [KO:K07604]
118025153  KRT13; keratin, type I cytoskeletal 13 [KO:K07604]
118025154  KRT9; LOW QUALITY PROTEIN: keratin, type I cytoskeletal 9 [KO:K07604]
118016198  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
118007599  GREB1; protein GREB1 [KO:K27477]
117998973  trefoil factor 1-like [KO:K22456]
118013416  PGR; progesterone receptor [KO:K08556]
118007998  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
118024863  RARA; retinoic acid receptor alpha isoform X1 [KO:K08527]
118002212  FOS; proto-oncogene c-Fos [KO:K04379]
118019356  JUN; transcription factor AP-1 [KO:K04448]
118008792  SP1; transcription factor Sp1 [KO:K04684]
117999272  GPER1; G-protein coupled estrogen receptor 1 [KO:K04246]
118023087  LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(s) subunit alpha-like [KO:K04632]
118024008  neuroendocrine secretory protein 55 [KO:K04632]
118024010  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
118011463  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
118023778  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
118011551  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
118016713  HBEGF; proheparin-binding EGF-like growth factor [KO:K08523]
118024512  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
118006264  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
118007652  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
118003693  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
118007016  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
118008901  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
118023800  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
118015219  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
118021775  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
118005070  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
118019227  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
118012101  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
118012308  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
117998657  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
118015807  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
118017967  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
118005189  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
118013832  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
118021134  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
118021299  CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
118027308  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
118024535  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
118013864  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
118004996  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
118026255  SHC3; SHC-transforming protein 3 [KO:K17448]
118002971  SHC4; SHC-transforming protein 4 [KO:K17449]
118024273  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
118007794  SOS1; son of sevenless homolog 1 [KO:K03099]
118002069  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
118016228  HRAS; GTPase HRas isoform X1 [KO:K02833]
118025572  KRAS; GTPase KRas isoform X1 [KO:K07827]
118000495  NRAS; GTPase NRas [KO:K07828]
118005431  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
118003336  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
118004882  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
117999637  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
117999826  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
118004424  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
118020028  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118006556  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
118016863  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
118019468  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
118006042  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
118022658  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118002024  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118014553  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118017906  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
117999714  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X1 [KO:K04615]
118019030  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
118005775  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
118020679  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
118023770  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
118012436  KCNJ3; G protein-activated inward rectifier potassium channel 1 [KO:K04997]
118000439  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
118013780  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
118013394  KCNJ5; G protein-activated inward rectifier potassium channel 4 isoform X1 [KO:K04999]
118007404  POMC; pro-opiomelanocortin [KO:K05228]
118001106  OPRM1; LOW QUALITY PROTEIN: mu-type opioid receptor [KO:K04215]
118005176  PRKCD; protein kinase C delta type isoform X1 [KO:K06068] [EC:2.7.11.13]
118026266  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
118015997  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
118003092  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
118011244  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
118011247  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
118005236  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
118025560  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
118001326  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
118008161  CALM2; calmodulin-2 [KO:K02183]
118016596  calmodulin-1-like [KO:K02183]
118002566  CALM1; calmodulin-1 [KO:K02183]
118003137  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
118012486  calmodulin-like [KO:K02183]
118019658  CALML6; calmodulin-like protein 6 [KO:K02183]
117998176  CALM3; calmodulin-3 [KO:K02183]
118020691  calmodulin-1-like [KO:K02183]
118021620  CALML3; calmodulin-like protein 3 [KO:K02183]
118021903  calmodulin-like [KO:K02183]
118026800  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
118001000  GRM1; metabotropic glutamate receptor 1 isoform X1 [KO:K04603]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00238  Potassium cation
C00334  4-Aminobutanoate
C00533  Nitric oxide
C00575  3',5'-Cyclic AMP
C00951  Estradiol-17beta
C01245  D-myo-Inositol 1,4,5-trisphosphate
Reference
PMID:16516516
  Authors
Zhang D, Trudeau VL
  Title
Integration of membrane and nuclear estrogen receptor signaling.
  Journal
Comp Biochem Physiol A Mol Integr Physiol 144:306-15 (2006)
DOI:10.1016/j.cbpa.2006.01.025
Reference
PMID:19187465
  Authors
Roepke TA, Qiu J, Bosch MA, Ronnekleiv OK, Kelly MJ
  Title
Cross-talk between membrane-initiated and nuclear-initiated oestrogen signalling in the hypothalamus.
  Journal
J Neuroendocrinol 21:263-70 (2009)
DOI:10.1111/j.1365-2826.2009.01846.x
Reference
PMID:19700741
  Authors
McCarthy MM
  Title
The two faces of estradiol: effects on the developing brain.
  Journal
Neuroscientist 15:599-610 (2009)
DOI:10.1177/1073858409340924
Reference
PMID:18538919
  Authors
Kelly MJ, Ronnekleiv OK
  Title
Membrane-initiated estrogen signaling in hypothalamic neurons.
  Journal
Mol Cell Endocrinol 290:14-23 (2008)
DOI:10.1016/j.mce.2008.04.014
Reference
PMID:16112267
  Authors
Kelly MJ, Qiu J, Ronnekleiv OK
  Title
Estrogen signaling in the hypothalamus.
  Journal
Vitam Horm 71:123-45 (2005)
DOI:10.1016/S0083-6729(05)71005-0
Reference
PMID:18253054
  Authors
Raz L, Khan MM, Mahesh VB, Vadlamudi RK, Brann DW
  Title
Rapid estrogen signaling in the brain.
  Journal
Neurosignals 16:140-53 (2008)
DOI:10.1159/000111559
Reference
PMID:15862823
  Authors
Malyala A, Kelly MJ, Ronnekleiv OK
  Title
Estrogen modulation of hypothalamic neurons: activation of multiple signaling pathways and gene expression changes.
  Journal
Steroids 70:397-406 (2005)
DOI:10.1016/j.steroids.2005.03.004
Reference
PMID:14573532
  Authors
Qiu J, Bosch MA, Tobias SC, Grandy DK, Scanlan TS, Ronnekleiv OK, Kelly MJ
  Title
Rapid signaling of estrogen in hypothalamic neurons involves a novel G-protein-coupled estrogen receptor that activates protein kinase C.
  Journal
J Neurosci 23:9529-40 (2003)
DOI:10.1523/JNEUROSCI.23-29-09529.2003
Reference
PMID:14993035
  Authors
Kelly MJ, Qiu J, Ronnekleiv OK
  Title
Estrogen modulation of G-protein-coupled receptor activation of potassium channels in the central nervous system.
  Journal
Ann N Y Acad Sci 1007:6-16 (2003)
DOI:10.1196/annals.1286.001
Reference
PMID:19549587
  Authors
Meyer MR, Haas E, Prossnitz ER, Barton M
  Title
Non-genomic regulation of vascular cell function and growth by estrogen.
  Journal
Mol Cell Endocrinol 308:9-16 (2009)
DOI:10.1016/j.mce.2009.03.009
Reference
PMID:20694192
  Authors
do Nascimento GR, Barros YV, Wells AK, Khalil RA
  Title
Research into Specific Modulators of Vascular Sex Hormone Receptors in the Management of Postmenopausal Cardiovascular Disease.
  Journal
Curr Hypertens Rev 5:283-306 (2009)
DOI:10.2174/157340209789587717
Reference
PMID:15695368
  Authors
Bjornstrom L, Sjoberg M
  Title
Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes.
  Journal
Mol Endocrinol 19:833-42 (2005)
DOI:10.1210/me.2004-0486
Reference
PMID:16270355
  Authors
Manavathi B, Kumar R
  Title
Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin.
  Journal
J Cell Physiol 207:594-604 (2006)
DOI:10.1002/jcp.20551
Reference
PMID:21844907
  Authors
Prossnitz ER, Barton M
  Title
The G-protein-coupled estrogen receptor GPER in health and disease.
  Journal
Nat Rev Endocrinol 7:715-26 (2011)
DOI:10.1038/nrendo.2011.122
Reference
PMID:21742056
  Authors
Meyer MR, Prossnitz ER, Barton M
  Title
The G protein-coupled estrogen receptor GPER/GPR30 as a regulator of cardiovascular function.
  Journal
Vascul Pharmacol 55:17-25 (2011)
DOI:10.1016/j.vph.2011.06.003
Reference
PMID:19767412
  Authors
Maggiolini M, Picard D
  Title
The unfolding stories of GPR30, a new membrane-bound estrogen receptor.
  Journal
J Endocrinol 204:105-14 (2010)
DOI:10.1677/JOE-09-0242
Reference
PMID:19464786
  Authors
Prossnitz ER, Maggiolini M
  Title
Mechanisms of estrogen signaling and gene expression via GPR30.
  Journal
Mol Cell Endocrinol 308:32-8 (2009)
DOI:10.1016/j.mce.2009.03.026
Reference
PMID:12650715
  Authors
Kelly MJ, Qiu J, Wagner EJ, Ronnekleiv OK
  Title
Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS).
  Journal
J Steroid Biochem Mol Biol 83:187-93 (2002)
DOI:10.1016/S0960-0760(02)00249-2
Reference
PMID:9278514
  Authors
Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS
  Title
Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites.
  Journal
Science 277:1508-10 (1997)
DOI:10.1126/science.277.5331.1508
Reference
PMID:12421825
  Authors
Razandi M, Pedram A, Park ST, Levin ER
  Title
Proximal events in signaling by plasma membrane estrogen receptors.
  Journal
J Biol Chem 278:2701-12 (2003)
DOI:10.1074/jbc.M205692200
Reference
PMID:18755790
  Authors
Roepke TA, Xue C, Bosch MA, Scanlan TS, Kelly MJ, Ronnekleiv OK
  Title
Genes associated with membrane-initiated signaling of estrogen and energy homeostasis.
  Journal
Endocrinology 149:6113-24 (2008)
DOI:10.1210/en.2008-0769
Reference
PMID:21779010
  Authors
Thomas C, Gustafsson JA
  Title
The different roles of ER subtypes in cancer biology and therapy.
  Journal
Nat Rev Cancer 11:597-608 (2011)
DOI:10.1038/nrc3093
Related
pathway
mlx04010  MAPK signaling pathway
mlx04020  Calcium signaling pathway
mlx04151  PI3K-Akt signaling pathway
mlx04270  Vascular smooth muscle contraction
mlx04727  GABAergic synapse
mlx04913  Ovarian steroidogenesis
KO pathway
ko04915   
LinkDB

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