Estrogen signaling pathway - Homo sapiens (human)
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.
Organismal Systems; Endocrine system
Pathway map Ortholog table
N00286 Nuclear-initiated estrogen signaling pathway
N01351 E2-ER-RAS-ERK signaling pathway
D00066 Progesterone (JP18/USP/INN)
D00105 Estradiol (JAN/USP/INN)
D00554 Ethinyl estradiol (USP)
D00575 Mestranol (JP18/USP/INN)
D00577 Diethylstilbestrol (USP/INN)
D00585 Mifepristone (JAN/USAN/INN)
D00946 Diethylstilbestrol diphosphate (USP)
D00949 Hydroxyprogesterone caproate (JAN/USP/INN)
D00950 Levonorgestrel (JAN/USP/INN)
D00951 Medroxyprogesterone acetate (JP18/USP)
D00952 Megestrol acetate (USP)
D00953 Norethindrone acetate (USP)
D00954 Norgestrel (JP18/USP/INN)
D00962 Clomiphene citrate (USP)
D00966 Tamoxifen citrate (JP18/USP)
D00967 Toremifene citrate (JAN/USAN)
D01159 Gestonorone caproate (JAN/USAN)
D01161 Fulvestrant (JAN/USP/INN)
D01217 Dydrogesterone (JP18/USP/INN)
D01294 Ethynodiol diacetate (JAN/USP)
D01299 Chlormadinone acetate (JP18/USAN)
D01374 Allylestrenol (JAN/INN)
D01413 Estradiol valerate (JAN/USP/INN)
D01414 Ethylestrenol (USAN/INN)
D01602 Mepitiostane (JP18/INN)
D01616 Sodium prasterone sulfate hydrate (JP18)
D01617 Estradiol dipropionate (JAN)
D01639 Tibolone (JAN/USAN/INN)
D01853 Miproxifene phosphate (JAN)
D01953 Estradiol benzoate (JP18/USP)
D01986 Estriol tripropionate (JAN)
D01989 Estriol diacetate benzoate (JAN)
D02018 Hexestrol diacetate (JAN)
D02217 Raloxifene hydrochloride (JAN/USP)
D02758 Acolbifene hydrochloride (USAN)
D02993 Arzoxifene hydrochloride (USAN)
D03062 Bazedoxifene acetate (JAN/USAN)
D03551 Clometherone (USAN/INN)
D03799 Dienogest (JAN/USAN/INN)
D03912 Droloxifene citrate (USAN)
D03917 Drospirenone (JAN/USP/INN)
D04061 Estradiol acetate (USAN)
D04063 Estradiol cypionate (USP)
D04064 Estradiol enanthate (USAN)
D04065 Estradiol undecylate (USAN/INN)
D04071 Estrogens, esterified (USP)
D04104 Etonogestrel (USAN/INN)
D04672 Lasofoxifene tartrate (JAN/USAN)
D04885 Medrogestone (USAN/INN)
D05106 Nafoxidine hydrochloride (USAN)
D05192 Nitromifene citrate (USAN)
D05679 Quingestanol acetate (USAN)
D05680 Quingestrone (USAN/INN)
D06235 Trimegestone (USAN/INN)
D06245 Trioxifene mesylate (USAN)
D06554 Alvespimycin hydrochloride (USAN)
D07434 Polyestradiol phosphate (INN)
D07826 Hexestrol diphosphate sodium
D07919 Estradiol 17 beta-hemisuccinate
D07921 Estriol sodium succinate (BAN)
D08052 Hydroxyprogesterone (INN)
D08053 Hydroxyprogesterone 17alfa-acetate
D08166 Medroxyprogesterone (INN)
D08281 Nomegestrol acetate (USAN)
D08285 Norethisterone enantate
D08958 Ospemifene (INN/USAN/BAN)
D09375 Retaspimycin (USAN/INN)
D09376 Retaspimycin hydrochloride (USAN)
D09687 Ulipristal acetate (JAN/USAN)
D09834 Levormeloxifene fumarate (JAN)
D10606 Raloxifene hydrochloride hydrate (JAN)
D10647 Luminespib mesylate (USAN)
D10876 Enclomiphene citrate (USAN)
D10986 Segesterone acetate (USAN)
D11181 Vilaprisan (JAN/USAN/INN)
D11264 Brilanestrant (USAN/INN)
D11672 Elacestrant hydrochloride (USAN)
D11766 Onalespib lactate (USAN)
D12145 Amcenestrant (JAN/USAN/INN)
Homo sapiens (human) [GN:
3320 HSP90AA1; heat shock protein 90 alpha family class A member 1 [KO: K04079]
3326 HSP90AB1; heat shock protein 90 alpha family class B member 1 [KO: K04079]
7184 HSP90B1; heat shock protein 90 beta family member 1 [KO: K09487]
3312 HSPA8; heat shock protein family A (Hsp70) member 8 [KO: K03283]
3303 HSPA1A; heat shock protein family A (Hsp70) member 1A [KO: K03283]
3306 HSPA2; heat shock protein family A (Hsp70) member 2 [KO: K03283]
3305 HSPA1L; heat shock protein family A (Hsp70) member 1 like [KO: K03283]
3304 HSPA1B; heat shock protein family A (Hsp70) member 1B [KO: K03283]
3310 HSPA6; heat shock protein family A (Hsp70) member 6 [KO: K03283]
10499 NCOA2; nuclear receptor coactivator 2 [KO: K11255]
596 BCL2; BCL2 apoptosis regulator [KO: K02161]
9166 EBAG9; estrogen receptor binding site associated antigen 9 [KO: K22455]
7039 TGFA; transforming growth factor alpha [KO: K08774]
5914 RARA; retinoic acid receptor alpha [KO: K08527]
2353 FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO: K04379]
3725 JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO: K04448]
2852 GPER1; G protein-coupled estrogen receptor 1 [KO: K04246]
1839 HBEGF; heparin binding EGF like growth factor [KO: K08523]
1385 CREB1; cAMP responsive element binding protein 1 [KO: K05870]
1386 ATF2; activating transcription factor 2 [KO: K04450]
468 ATF4; activating transcription factor 4 [KO: K04374]
10488 CREB3; cAMP responsive element binding protein 3 [KO: K09048]
90993 CREB3L1; cAMP responsive element binding protein 3 like 1 [KO: K09048]
64764 CREB3L2; cAMP responsive element binding protein 3 like 2 [KO: K09048]
84699 CREB3L3; cAMP responsive element binding protein 3 like 3 [KO: K09048]
148327 CREB3L4; cAMP responsive element binding protein 3 like 4 [KO: K09048]
9586 CREB5; cAMP responsive element binding protein 5 [KO: K09047]
1388 ATF6B; activating transcription factor 6 beta [KO: K09049]
2885 GRB2; growth factor receptor bound protein 2 [KO: K04364]
6654 SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO: K03099]
6655 SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO: K03099]
3265 HRAS; HRas proto-oncogene, GTPase [KO: K02833]
3845 KRAS; KRAS proto-oncogene, GTPase [KO: K07827]
4893 NRAS; NRAS proto-oncogene, GTPase [KO: K07828]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO: K00922] [EC: 126.96.36.199]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO: K00922] [EC: 188.8.131.52]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO: K00922] [EC: 184.108.40.206]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO: K02649]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO: K02649]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO: K02649]
2550 GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO: K04615]
9568 GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO: K04615]
2770 GNAI1; G protein subunit alpha i1 [KO: K04630]
2773 GNAI3; G protein subunit alpha i3 [KO: K04630]
2771 GNAI2; G protein subunit alpha i2 [KO: K04630]
2775 GNAO1; G protein subunit alpha o1 [KO: K04534]
3760 KCNJ3; potassium inwardly rectifying channel subfamily J member 3 [KO: K04997]
3763 KCNJ6; potassium inwardly rectifying channel subfamily J member 6 [KO: K05000]
3765 KCNJ9; potassium inwardly rectifying channel subfamily J member 9 [KO: K05002]
3762 KCNJ5; potassium inwardly rectifying channel subfamily J member 5 [KO: K04999]
3708 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO: K04958]
3709 ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO: K04959]
3710 ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO: K04960]
2911 GRM1; glutamate metabotropic receptor 1 [KO: K04603]
C01245 D-myo-Inositol 1,4,5-trisphosphate
Zhang D, Trudeau VL
Integration of membrane and nuclear estrogen receptor signaling.
Roepke TA, Qiu J, Bosch MA, Ronnekleiv OK, Kelly MJ
Cross-talk between membrane-initiated and nuclear-initiated oestrogen signalling in the hypothalamus.
The two faces of estradiol: effects on the developing brain.
Kelly MJ, Ronnekleiv OK
Membrane-initiated estrogen signaling in hypothalamic neurons.
Kelly MJ, Qiu J, Ronnekleiv OK
Estrogen signaling in the hypothalamus.
Raz L, Khan MM, Mahesh VB, Vadlamudi RK, Brann DW
Rapid estrogen signaling in the brain.
Malyala A, Kelly MJ, Ronnekleiv OK
Estrogen modulation of hypothalamic neurons: activation of multiple signaling pathways and gene expression changes.
Qiu J, Bosch MA, Tobias SC, Grandy DK, Scanlan TS, Ronnekleiv OK, Kelly MJ
Rapid signaling of estrogen in hypothalamic neurons involves a novel G-protein-coupled estrogen receptor that activates protein kinase C.
Kelly MJ, Qiu J, Ronnekleiv OK
Estrogen modulation of G-protein-coupled receptor activation of potassium channels in the central nervous system.
Meyer MR, Haas E, Prossnitz ER, Barton M
Non-genomic regulation of vascular cell function and growth by estrogen.
do Nascimento GR, Barros YV, Wells AK, Khalil RA
Research into Specific Modulators of Vascular Sex Hormone Receptors in the Management of Postmenopausal Cardiovascular Disease.
Bjornstrom L, Sjoberg M
Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes.
Manavathi B, Kumar R
Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin.
Prossnitz ER, Barton M
The G-protein-coupled estrogen receptor GPER in health and disease.
Meyer MR, Prossnitz ER, Barton M
The G protein-coupled estrogen receptor GPER/GPR30 as a regulator of cardiovascular function.
Maggiolini M, Picard D
The unfolding stories of GPR30, a new membrane-bound estrogen receptor.
Prossnitz ER, Maggiolini M
Mechanisms of estrogen signaling and gene expression via GPR30.
Kelly MJ, Qiu J, Wagner EJ, Ronnekleiv OK
Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS).
Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS
Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites.
Razandi M, Pedram A, Park ST, Levin ER
Proximal events in signaling by plasma membrane estrogen receptors.
Roepke TA, Xue C, Bosch MA, Scanlan TS, Kelly MJ, Ronnekleiv OK
Genes associated with membrane-initiated signaling of estrogen and energy homeostasis.
Thomas C, Gustafsson JA
The different roles of ER subtypes in cancer biology and therapy.
hsa04270 Vascular smooth muscle contraction
LinkDB All DBs