KEGG   PATHWAY: uah04915
Entry
uah04915                    Pathway                                
Name
Estrogen signaling pathway - Ursus arctos (brown bear)
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
uah04915  Estrogen signaling pathway
uah04915

Other DBs
GO: 0030520
Organism
Ursus arctos (brown bear) [GN:uah]
Gene
113259567  ESR1; estrogen receptor [KO:K08550]
113246310  ESR2; estrogen receptor beta [KO:K08551]
113261246  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
113267248  HSP90AA1; heat shock protein HSP 90-alpha [KO:K04079]
113256067  HSP90B1; endoplasmin [KO:K09487]
113243846  FKBP5; peptidyl-prolyl cis-trans isomerase FKBP5 [KO:K09571] [EC:5.2.1.8]
113258022  FKBP4; peptidyl-prolyl cis-trans isomerase FKBP4 isoform X2 [KO:K09571] [EC:5.2.1.8]
113250194  heat shock 70 kDa protein 1 [KO:K03283]
113250195  heat shock 70 kDa protein 1 [KO:K03283]
113243744  heat shock 70 kDa protein 1-like [KO:K03283]
113268759  HSPA6; LOW QUALITY PROTEIN: heat shock 70 kDa protein 6 [KO:K03283]
113259928  HSPA8; heat shock cognate 71 kDa protein isoform X2 [KO:K03283]
113270535  NCOA1; nuclear receptor coactivator 1 isoform X1 [KO:K09101] [EC:2.3.1.48]
113253067  NCOA2; nuclear receptor coactivator 2 isoform X1 [KO:K11255]
113258689  NCOA3; nuclear receptor coactivator 3 isoform X1 [KO:K11256] [EC:2.3.1.48]
113253490  BCL2; apoptosis regulator Bcl-2 isoform X3 [KO:K02161]
113252813  EBAG9; receptor-binding cancer antigen expressed on SiSo cells isoform X1 [KO:K22455]
113265681  keratin, type I cytoskeletal 42 [KO:K07604]
113265475  KRT24; keratin, type I cytoskeletal 24 [KO:K07604]
113265476  KRT12; keratin, type I cytoskeletal 12 [KO:K07604]
113265477  KRT20; keratin, type I cytoskeletal 20 [KO:K07604]
113265172  keratin, type I cytoskeletal 17 [KO:K07604]
113265174  keratin, type I cytoskeletal 13 [KO:K07604]
113265175  KRT36; keratin, type I cuticular Ha6 [KO:K07604]
113265176  keratin, type I cuticular Ha7-like [KO:K07604]
113265177  keratin, type I cuticular Ha8-like [KO:K07604]
113249586  keratin, type I cuticular Ha1-like [KO:K07604]
113249587  KRT34; keratin, type I cuticular Ha4 [KO:K07604]
113265449  keratin, type I cytoskeletal 16 isoform X2 [KO:K07604]
113265450  keratin, type I cytoskeletal 14 [KO:K07604]
113265451  LOW QUALITY PROTEIN: keratin, type I cytoskeletal 15 [KO:K07604]
113265452  keratin, type I cytoskeletal 19 [KO:K07604]
113265453  KRT35; LOW QUALITY PROTEIN: keratin, type I cuticular Ha5 [KO:K07604]
113265454  KRT32; keratin, type I cuticular Ha2 [KO:K07604]
113265455  KRT38; keratin, type I cuticular Ha8 [KO:K07604]
113265457  KRT23; keratin, type I cytoskeletal 23 [KO:K07604]
113265458  keratin, type I cuticular Ha1 [KO:K07604]
113265464  KRT39; keratin, type I cytoskeletal 39 [KO:K07604]
113265465  KRT40; keratin, type I cytoskeletal 40 [KO:K07604]
113265469  KRT10; keratin, type I cytoskeletal 10 isoform X1 [KO:K07604]
113265470  KRT28; keratin, type I cytoskeletal 28 [KO:K07604]
113265471  keratin, type I cytoskeletal 26 [KO:K07604]
113265472  KRT25; keratin, type I cytoskeletal 25 [KO:K07604]
113265473  KRT27; keratin, type I cytoskeletal 27 [KO:K07604]
125281112  keratin, type I cuticular Ha3-I [KO:K07604]
113265173  KRT9; keratin, type I cytoskeletal 9 [KO:K07604]
113243953  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
113269999  GREB1; protein GREB1 [KO:K27477]
113256792  TFF1; trefoil factor 1 [KO:K22456]
113259802  PGR; progesterone receptor isoform X1 [KO:K08556]
113268295  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
113265491  RARA; retinoic acid receptor alpha isoform X1 [KO:K08527]
113270317  FOS; protein c-Fos [KO:K04379]
113254611  JUN; transcription factor Jun [KO:K04448]
113247719  GPER1; G-protein coupled estrogen receptor 1 [KO:K04246]
113258768  GNAS; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas [KO:K04632]
113258223  neuroendocrine secretory protein 55 [KO:K04632]
113258578  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
113252249  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
113258671  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
113261821  HBEGF; proheparin-binding EGF-like growth factor [KO:K08523]
113257705  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
113260807  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
113270586  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
113246056  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
113252326  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
113257671  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
113252223  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
113252717  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
113270857  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
113254486  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
113247197  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
113250525  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
113250749  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
113241758  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
113264990  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
113264732  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
113245324  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
113260470  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
113242823  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X2 [KO:K09048]
113262153  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X2 [KO:K09047]
113243741  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
113257444  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
113245295  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
113242690  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
113270120  SHC3; SHC-transforming protein 3 [KO:K17448]
113269597  SHC4; SHC-transforming protein 4 [KO:K17449]
113244637  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
113266205  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
113241630  SOS1; LOW QUALITY PROTEIN: son of sevenless homolog 1 [KO:K03099]
125282300  HRAS; GTPase HRas isoform X1 [KO:K02833]
113257792  KRAS; GTPase KRas isoform X1 [KO:K07827]
113244394  NRAS; GTPase NRas isoform X2 [KO:K07828]
113257190  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
113240885  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
113242822  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
113267646  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
113247020  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
113254799  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
113270537  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
113253989  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
113256705  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
113254730  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
113255266  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
113267192  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
113243572  AKT2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
113262966  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
113249565  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X1 [KO:K04615]
113260410  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
113259201  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
113244920  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
113256902  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
113252256  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X2 [KO:K04534]
113250873  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
113258629  G protein-activated inward rectifier potassium channel 2 [KO:K05000]
113246727  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
113259740  KCNJ5; G protein-activated inward rectifier potassium channel 4 isoform X1 [KO:K04999]
113268582  POMC; pro-opiomelanocortin [KO:K05228]
113259577  OPRM1; LOW QUALITY PROTEIN: mu-type opioid receptor [KO:K04215]
113256975  PRKCD; protein kinase C delta type isoform X1 [KO:K06068] [EC:2.7.11.13]
113269831  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
113244175  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
113258346  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
113242038  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
113258243  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
113257114  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
113257782  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
113243814  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
113241090  calmodulin-like [KO:K02183]
113241128  calmodulin-like protein 3 [KO:K02183]
113240902  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
113256068  calmodulin-1-like [KO:K02183]
113243394  CALM3; calmodulin-3 [KO:K02183]
113245972  CALM2; calmodulin-2 [KO:K02183]
113267365  CALM1; calmodulin-1 isoform X2 [KO:K02183]
113270682  CALML6; calmodulin-like protein 6 [KO:K02183]
113241474  NOS3; nitric oxide synthase, endothelial isoform X2 [KO:K13242] [EC:1.14.13.39]
113259527  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
uah04010  MAPK signaling pathway
uah04020  Calcium signaling pathway
uah04151  PI3K-Akt signaling pathway
uah04270  Vascular smooth muscle contraction
uah04727  GABAergic synapse
uah04913  Ovarian steroidogenesis
KO pathway
ko04915   
LinkDB

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