KEGG   PATHWAY: mmu04915
Entry
mmu04915                    Pathway                                
Name
Estrogen signaling pathway - Mus musculus (house mouse)
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
mmu04915  Estrogen signaling pathway
mmu04915

Other DBs
GO: 0030520
Organism
Mus musculus (house mouse) [GN:mmu]
Gene
104110  Adcy4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
104111  Adcy3; adenylate cyclase type 3 isoform 1 [KO:K08043] [EC:4.6.1.1]
107656  Krt9; keratin, type I cytoskeletal 9 [KO:K07604]
110157  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform 1 [KO:K04366] [EC:2.7.11.1]
11512  Adcy6; adenylate cyclase type 6 isoform 2 [KO:K08046] [EC:4.6.1.1]
11513  Adcy7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
11514  Adcy8; adenylate cyclase type 8 isoform 1 [KO:K08048] [EC:4.6.1.1]
11515  Adcy9; adenylate cyclase type 9 isoform 1 [KO:K08049] [EC:4.6.1.1]
11651  Akt1; RAC-alpha serine/threonine-protein kinase isoform 1 [KO:K04456] [EC:2.7.11.1]
11652  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
11909  Atf2; cyclic AMP-dependent transcription factor ATF-2 isoform 1 [KO:K04450]
11911  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
12043  Bcl2; apoptosis regulator Bcl-2 isoform 1 [KO:K02161]
12313  Calm1; calmodulin-1 isoform 2 [KO:K02183]
12314  Calm2; calmodulin-2 isoform 1 [KO:K02183]
12315  Calm3; calmodulin-3 [KO:K02183]
12912  Creb1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870]
12913  Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
12915  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
13033  Ctsd; cathepsin D precursor [KO:K01379] [EC:3.4.23.5]
13649  Egfr; epidermal growth factor receptor isoform 1 precursor [KO:K04361] [EC:2.7.10.1]
13982  Esr1; estrogen receptor isoform 1 [KO:K08550]
13983  Esr2; estrogen receptor beta isoform 2 [KO:K08551]
14228  Fkbp4; peptidyl-prolyl cis-trans isomerase FKBP4 [KO:K09571] [EC:5.2.1.8]
14229  Fkbp5; peptidyl-prolyl cis-trans isomerase FKBP5 [KO:K09571] [EC:5.2.1.8]
14281  Fos; protein c-Fos [KO:K04379]
14677  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
14678  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
14679  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
14681  Gnao1; guanine nucleotide-binding protein G(o) subunit alpha isoform B [KO:K04534]
14682  Gnaq; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
14683  Gnas; protein GNAS isoform XLas [KO:K04632]
14784  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
14816  Grm1; metabotropic glutamate receptor 1 isoform alpha precursor [KO:K04603]
15200  Hbegf; proheparin-binding EGF-like growth factor precursor [KO:K08523]
15461  Hras; GTPase HRas isoform 1 [KO:K02833]
15481  Hspa8; heat shock cognate 71 kDa protein isoform 1 [KO:K03283]
15482  Hspa1l; heat shock 70 kDa protein 1-like [KO:K03283]
15511  Hspa1b; heat shock 70 kDa protein 1B [KO:K03283]
15516  Hsp90ab1; heat shock protein HSP 90-beta [KO:K04079]
15519  Hsp90aa1; heat shock protein HSP 90-alpha [KO:K04079]
16438  Itpr1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
16439  Itpr2; inositol 1,4,5-trisphosphate receptor type 2 isoform 1 [KO:K04959]
16440  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
16476  Jun; transcription factor Jun [KO:K04448]
16519  Kcnj3; G protein-activated inward rectifier potassium channel 1 isoform 1 [KO:K04997]
16521  Kcnj5; G protein-activated inward rectifier potassium channel 4 isoform 1 [KO:K04999]
16522  Kcnj6; G protein-activated inward rectifier potassium channel 2 isoform Girk2-1 [KO:K05000]
16524  Kcnj9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
16653  Kras; GTPase KRas isoform 2 [KO:K07827]
16660  Krt31; keratin, type I cuticular Ha1 [KO:K07604]
16661  Krt10; keratin, type I cytoskeletal 10 [KO:K07604]
16663  Krt13; keratin, type I cytoskeletal 13 isoform 1 [KO:K07604]
16664  Krt14; keratin, type I cytoskeletal 14 isoform 1 [KO:K07604]
16665  Krt15; keratin, type I cytoskeletal 15 [KO:K07604]
16666  Krt16; keratin, type I cytoskeletal 16 isoform 2 [KO:K07604]
16667  Krt17; keratin, type I cytoskeletal 17 [KO:K07604]
16668  Krt18; keratin, type I cytoskeletal 18 [KO:K07604]
16669  Krt19; keratin, type I cytoskeletal 19 isoform 1 [KO:K07604]
16670  Krt32; keratin, type I cuticular Ha2 [KO:K07604]
16671  Krt33b; keratin, type I cuticular Ha3-II [KO:K07604]
16672  Krt34; keratin, type I cuticular Ha4 [KO:K07604]
16673  Krt36; keratin, type I cuticular Ha6 [KO:K07604]
16675  Krt27; keratin, type I cytoskeletal 27 [KO:K07604]
17390  Mmp2; 72 kDa type IV collagenase preproprotein [KO:K01398] [EC:3.4.24.24]
17395  Mmp9; matrix metalloproteinase-9 preproprotein [KO:K01403] [EC:3.4.24.35]
17977  Ncoa1; nuclear receptor coactivator 1 isoform 2 [KO:K09101] [EC:2.3.1.48]
17978  Ncoa2; nuclear receptor coactivator 2 isoform a [KO:K11255]
17979  Ncoa3; nuclear receptor coactivator 3 isoform 2 [KO:K11256] [EC:2.3.1.48]
18127  Nos3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
18176  Nras; GTPase NRas [KO:K07828]
18390  Oprm1; mu-type opioid receptor isoform MOR-1 [KO:K04215]
18667  Pgr; progesterone receptor [KO:K08556]
18706  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
18707  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform a [KO:K00922] [EC:2.7.1.153]
18708  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform 2 [KO:K02649]
18709  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform 1 [KO:K02649]
18710  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform 1 [KO:K02649]
18747  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha isoform 1 [KO:K04345] [EC:2.7.11.11]
18749  Prkacb; cAMP-dependent protein kinase catalytic subunit beta isoform 1 [KO:K04345] [EC:2.7.11.11]
18753  Prkcd; protein kinase C delta type isoform 2 [KO:K06068] [EC:2.7.11.13]
18795  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform 1 [KO:K05858] [EC:3.1.4.11]
18796  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform a [KO:K05858] [EC:3.1.4.11]
18797  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform a [KO:K05858] [EC:3.1.4.11]
18798  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform a [KO:K05858] [EC:3.1.4.11]
18976  Pomc; pro-opiomelanocortin preproprotein [KO:K05228]
193740  Hspa1a; heat shock 70 kDa protein 1A [KO:K03283]
19401  Rara; retinoic acid receptor alpha isoform 1 [KO:K08527]
20416  Shc1; SHC-transforming protein 1 isoform a [KO:K06279]
20418  Shc3; SHC-transforming protein 3 [KO:K17448]
20662  Sos1; son of sevenless homolog 1 [KO:K03099]
20663  Sos2; son of sevenless homolog 2 [KO:K03099]
20683  Sp1; transcription factor Sp1 [KO:K04684]
20779  Src; proto-oncogene tyrosine-protein kinase Src isoform 2 [KO:K05704] [EC:2.7.10.2]
208647  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
208677  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
210044  Adcy2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
216148  Shc2; SHC-transforming protein 2 [KO:K17447]
21784  Tff1; trefoil factor 1 precursor [KO:K22456]
21802  Tgfa; protransforming growth factor alpha isoform 1 preproprotein [KO:K08774]
22027  Hsp90b1; endoplasmin precursor [KO:K09487]
224129  Adcy5; adenylate cyclase type 5 isoform 1 [KO:K08045] [EC:4.6.1.1]
231991  Creb5; cyclic AMP-responsive element-binding protein 5 isoform 1 [KO:K09047]
237934  Krt39; keratin, type I cytoskeletal 39 [KO:K07604]
23797  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
242425  Gabbr2; gamma-aminobutyric acid type B receptor subunit 2 precursor [KO:K04615]
26395  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform 1 [KO:K04368] [EC:2.7.12.2]
26396  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform 1 [KO:K04369] [EC:2.7.12.2]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
26427  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
268482  Krt12; keratin, type I cytoskeletal 12 [KO:K07604]
268527  Greb1; protein GREB1 isoform 1 [KO:K27477]
271849  Shc4; SHC-transforming protein 4 [KO:K17449]
320864  Krt26; keratin, type I cytoskeletal 26 [KO:K07604]
406221  Krt40; keratin, type I cytoskeletal 40 isoform 1 [KO:K07604]
432530  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
494124  Calm5; calmodulin 5 [KO:K02183]
53617  Krt35; keratin, type I cuticular Ha5 [KO:K07604]
54393  Gabbr1; gamma-aminobutyric acid type B receptor subunit 1 isoform 1 precursor [KO:K04615]
55960  Ebag9; receptor-binding cancer antigen expressed on SiSo cells [KO:K22455]
66809  Krt20; keratin, type I cytoskeletal 20 [KO:K07604]
68239  Krt42; keratin, type I cytoskeletal 42 [KO:K07604]
70405  Calml3; calmodulin-like protein 3 [KO:K02183]
70810  Krt25; keratin, type I cytoskeletal 25 [KO:K07604]
70843  Krt28; keratin, type I cytoskeletal 28 [KO:K07604]
71888  Krt33a; keratin, type I cuticular Ha3-I [KO:K07604]
74769  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
75600  Calml4; calmodulin-like protein 4 isoform a [KO:K02183]
75706  Krt24; keratin, type I cytoskeletal 24 [KO:K07604]
76854  Gper1; G-protein coupled estrogen receptor 1 [KO:K04246]
78284  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform 1 [KO:K09048]
80796  Calm4; calmodulin-4 [KO:K02183]
94179  Krt23; keratin, type I cytoskeletal 23 [KO:K07604]
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
mmu04010  MAPK signaling pathway
mmu04020  Calcium signaling pathway
mmu04151  PI3K-Akt signaling pathway
mmu04270  Vascular smooth muscle contraction
mmu04727  GABAergic synapse
mmu04913  Ovarian steroidogenesis
KO pathway
ko04915   

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