KEGG   PATHWAY: rno04915
Entry
rno04915                    Pathway                                
Name
Estrogen signaling pathway - Rattus norvegicus (rat)
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
rno04915  Estrogen signaling pathway
rno04915

Other DBs
GO: 0030520
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
108348108  Hspa1b; heat shock 70 kDa protein 1B [KO:K03283]
114858  Shc3; SHC-transforming protein 3 [KO:K17448]
116560  Kcnj9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
117270  Tff1; trefoil factor 1 precursor [KO:K22456]
134484121  [KO:K00922] [EC:2.7.1.153]
170538  Prkcd; protein kinase C delta type [KO:K06068] [EC:2.7.11.13]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
171104  Gper1; G-protein coupled estrogen receptor 1 [KO:K04246]
171293  Ctsd; cathepsin D precursor [KO:K01379] [EC:3.4.23.5]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
24224  Bcl2; apoptosis regulator Bcl-2 [KO:K02161]
24242  Calm1; calmodulin-1 [KO:K02183]
24244  Calm3; calmodulin-3 [KO:K02183]
24329  Egfr; epidermal growth factor receptor isoform 2 precursor [KO:K04361] [EC:2.7.10.1]
24414  Grm1; metabotropic glutamate receptor 1 isoform alpha precursor [KO:K04603]
24468  Hspa8; heat shock cognate 71 kDa protein [KO:K03283]
24472  Hspa1a; heat shock 70 kDa protein 1A [KO:K03283]
24516  Jun; transcription factor Jun [KO:K04448]
24525  Kras; GTPase KRas [KO:K07827]
24600  Nos3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
24605  Nras; GTPase NRas [KO:K07828]
24654  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
24664  Pomc; pro-opiomelanocortin precursor [KO:K05228]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
24705  Rara; retinoic acid receptor alpha [KO:K08527]
24790  Sp1; transcription factor Sp1 [KO:K04684]
24827  Tgfa; protransforming growth factor alpha preproprotein [KO:K08774]
24890  Esr1; estrogen receptor [KO:K08550]
24896  Gnas; SCG6 (secretogranin VI) isoform SCG6 precursor [KO:K04632]
24963  Hspa1l; heat shock 70 kDa protein 1-like [KO:K03283]
25031  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
25149  Esr2; estrogen receptor beta [KO:K08551]
25154  Pgr; progesterone receptor [KO:K08556]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25262  Itpr1; inositol 1,4,5-trisphosphate receptor type 1 isoform 3 [KO:K04958]
25289  Adcy6; adenylate cyclase type 6 isoform 2 [KO:K08046] [EC:4.6.1.1]
25433  Hbegf; proheparin-binding EGF-like growth factor precursor [KO:K08523]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
25601  Oprm1; mu-type opioid receptor isoform 1 [KO:K04215]
25636  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
25643  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
25679  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
25686  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
25743  Kcnj6; G protein-activated inward rectifier potassium channel 2 isoform 1 [KO:K05000]
260321  Fkbp4; peptidyl-prolyl cis-trans isomerase FKBP4 [KO:K09571] [EC:5.2.1.8]
266717  Krt9; keratin, type I cytoskeletal 9 [KO:K07604]
286912  Krt20; keratin, type I cytoskeletal 20 [KO:K07604]
287675  Krt24; keratin, type I cytoskeletal 24 [KO:K07604]
287678  Krt23; keratin, type I cytoskeletal 23 [KO:K07604]
287679  Krt40; keratin, type I cytoskeletal 40 [KO:K07604]
287697  Krt35; keratin, type I cuticular Ha5 [KO:K07604]
287698  Krt36; keratin, type I cuticular Ha6 [KO:K07604]
287699  Krt13; keratin, type I cytoskeletal 13 [KO:K07604]
287700  Krt15; keratin, type I cytoskeletal 15 [KO:K07604]
287701  Krt14; keratin, type I cytoskeletal 14 [KO:K07604]
287702  Krt17; keratin, type I cytoskeletal 17 [KO:K07604]
29241  Adcy8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
29322  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
293508  Prkacb; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
293621  Hras; GTPase HRas [KO:K02833]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
294853  Krt18; keratin, type I cytoskeletal 18 [KO:K07604]
29713  Kcnj5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
298400  Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
299331  Hsp90aa1; heat shock protein HSP 90-alpha [KO:K04079]
299864  Ebag9; receptor-binding cancer antigen expressed on SiSo cells [KO:K22455]
301252  Hsp90ab1; heat shock protein HSP 90-beta [KO:K04079]
302950  Adcy9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
303519  Krt25; keratin, type I cytoskeletal 25 [KO:K07604]
303523  Krt39; keratin, type I cytoskeletal 39 [KO:K07604]
303527  Krt33a; keratin, type I cuticular Ha3-I [KO:K07604]
303528  Krt34; keratin, type I cuticular Ha4 [KO:K07604]
303530  Krt16; keratin, type I cytoskeletal 16 [KO:K07604]
305509  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
307100  Calml3; calmodulin-like protein 3 [KO:K02183]
310616  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform 1 [KO:K09048]
313845  Sos1; son of sevenless homolog 1 [KO:K03099]
313929  Ncoa1; nuclear receptor coactivator 1 [KO:K09101] [EC:2.3.1.48]
314322  Fos; protein c-Fos [KO:K04379]
314612  Shc2; SHC-transforming protein 2 [KO:K17447]
314638  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
360623  Krt28; keratin, type I cytoskeletal 28 isoform 2 [KO:K07604]
360625  Krt12; keratin, type I cytoskeletal 12 [KO:K07604]
360626  Krt19; keratin, type I cytoskeletal 19 [KO:K07604]
361810  Fkbp5; peptidyl-prolyl cis-trans isomerase FKBP5 [KO:K09571] [EC:5.2.1.8]
362165  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
362339  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
362862  Hsp90b1; endoplasmin precursor [KO:K09487]
364774  Calml5; calmodulin-like protein 5 [KO:K02183]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
367858  Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833]
406169  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
407758  Krt26; keratin, type I cytoskeletal 26 [KO:K07604]
450225  Krt10; keratin, type I cytoskeletal 10 [KO:K07604]
450226  Ka11; type I keratin KA11 [KO:K07604]
450227  Krt33b; keratin, type I cuticular Ha3-II [KO:K07604]
450228  Krt31; keratin, type I cuticular Ha1 [KO:K07604]
450229  Krt27; keratin, type I cytoskeletal 27 [KO:K07604]
450230  Krt32; keratin, type I cuticular Ha2 [KO:K07604]
450231  Krt42; keratin, type I cytoskeletal 42 [KO:K07604]
500131  Creb5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
500633  Greb1; growth regulating estrogen receptor binding 1 [KO:K27477]
50599  Kcnj3; G protein-activated inward rectifier potassium channel 1 [KO:K04997]
50663  Calm2; calmodulin-2 [KO:K02183]
50664  Gnao1; guanine nucleotide-binding protein G(o) subunit alpha isoform B [KO:K04534]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
54223  Adcy4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
58960  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
64508  Adcy3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
64532  Adcy5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
679845  Shc4; SHC-transforming protein 4 [KO:K17449]
680121  Haus8l2; heat shock cognate 71 kDa protein-like [KO:K03283]
683212  Krt18l1; keratin, type I cytoskeletal 18-like [KO:K07604]
691455  Calml4; calmodulin-like protein 4 [KO:K02183]
79255  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
81504  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
81636  Adcy2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
81646  Creb1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870]
81647  Atf2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
81657  Gabbr1; gamma-aminobutyric acid type B receptor subunit 1 precursor [KO:K04615]
81664  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
81666  Gnaq; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
81678  Itpr2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
81686  Mmp2; 72 kDa type IV collagenase precursor [KO:K01398] [EC:3.4.24.24]
81687  Mmp9; matrix metalloproteinase-9 precursor [KO:K01403] [EC:3.4.24.35]
83633  Gabbr2; gamma-aminobutyric acid type B receptor subunit 2 precursor [KO:K04615]
83724  Ncoa2; nuclear receptor coactivator 2 [KO:K11255]
83805  Src; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
84420  Adcy7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
84584  Ncoa3; nuclear receptor coactivator 3 [KO:K11256] [EC:2.3.1.48]
85240  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
85384  Sos2; son of sevenless homolog 2 [KO:K03099]
85385  Shc1; SHC-transforming protein 1 isoform b [KO:K06279]
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
rno04010  MAPK signaling pathway
rno04020  Calcium signaling pathway
rno04151  PI3K-Akt signaling pathway
rno04270  Vascular smooth muscle contraction
rno04727  GABAergic synapse
rno04913  Ovarian steroidogenesis
KO pathway
ko04915   

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