Extra-nuclear estrogen signaling (Homo sapiens)

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10, 20, 28, 33, 39...79, 82, 124, 15068, 71, 12124, 37, 41, 81, 93...29, 14910, 19-21, 33...36, 59, 92, 143, 145...12, 14, 19, 23, 47...13, 14, 19, 47, 71...20, 53, 90, 117, 123...24, 37, 41, 93, 112...20, 28, 34, 35, 67...95, 127, 130, 14447, 68, 99, 121, 1289, 13, 14, 19, 47...64, 65, 104, 111666618, 21, 31, 32, 47...9, 11, 13, 25, 45...84, 90, 117, 140, 14195, 127, 130, 14447, 128, 13312112, 49, 85, 87, 92...14, 19, 47, 101, 105...10512, 49, 64, 65, 87...4, 71, 72, 1307316, 26, 125, 14213, 105, 10638, 51, 64, 65, 104...42, 48, 50, 52, 60...10020, 47, 53, 13334, 61, 117, 14030, 42, 60, 69, 126...nucleoplasmmitochondrial outer membraneGolgi lumencytosolMMP3(100-477) GNG11 Me260-ESR1:STRN:ESTG: MyrG-pY419 SRC:PI3Kalpha:pY-PTK2G-protein beta-gammacomplexZDHHC7 AdoMetHSBP1 oligomerPalmS-ESR2 S-Farn-Me-PalmS KRAS4A pY-PTK2 FOS geneSTRN PalmS-ESRsp-S133-CREB1 PIK3CA PRKCZATPPI(3,4,5)P3 GNAI1 S1PR3ER alpha46 p-S133-CREB1ZDHHC21 Me-PalmS-ESR2 S1PPIK3R3 GNB3 Me260-ESR1 PDPK1 PI3K alphap-T32,S253,S315-FOXO3S1P S-Farn-Me KRAS4B p-T305,S472-AKT3 PalmS-ESR2 STRN p-Y185,Y187 MAPK1dimerSHC1-2 p-Y397-PTK2 GNAI1 p-Y1161,Y1165,Y1166-IGF1R(741-1367) PIK3R1 p-S133-CREB1 p-T185,Y187-MAPK1 EPGN(23-154) STRN GNG8 PalmS-ER alpha46 PalmS-ESRsMe87-PalmS-ER alpha36 GNG13 ESR1 p-4S,T336-ELK1HBEGF(63-148)PDPK1:PIP3:pS,p-T410 PRKCZ:p21RAS:GDPER alpha36 GNG11 GTP PalmS-ER alpha46 ADPGNGT2 STRN S-Farn-Me KRAS4B PIK3CA Me260-PalmS-ESR1 GNG13 PalmS-ESR1 S-Farn-Me-2xPalmS HRAS GNG13 ESR2 Me87-PalmS-ER alpha36 PRKCZ STRNGNB3 HBEGF(63-148) FOXO3ER alpha46 ESRs:STRN:ESTG:MyrG-pY419 SRC:PI3K alphaPIK3R3 GNAI1 GNAI3 p-6Y-EGFR STRN PIK3R1 PI(3,4,5)P3 AREG(101-187) GNG7 ATPSTRN ESTG S-Farn-Me PalmS NRAS FOSgene:SRF:p-4S,T336ELK1MyrG-p-Y419-SRC pS, p-T410-PRKCZ GNB2 BH4 ADMAESTG GNAI2 Me260-PalmS-ESR1 SHC1-3 PTK2GDP GDP ADPBTC(32-111) Me-PalmS-ESRsGNG7 IGF1R(31-736) EREG(60-108) ZDHHC7, ZDHHC21ESR2 ESR1 MMP2(110-660) PI(3,4,5)P3 FOSBCL2HeterotrimericG-protein Gi(inactive)S-Farn-Me PalmS NRAS PALM-CoAGNG5 EREG(60-108) S-Farn-Me-PalmS KRAS4A p-6Y-EGFR CAV2 PTK2 GNB5 p-T308,S473-AKT1 MMP9(107-707) pS, p-T410-PRKCZ GNG10 CAVsp-T410-PRKCZ SHC1-3 PalmS-ESRs:STRN:ESTGIGF1R(31-736) p-6Y-EGFR ER alpha46 ESR2 CCND1 gene GNAT3 STRN ESTG GNB5 SPGGNB2 CCND1FOS gene MyrG-p-Y419-SRC GNB2 ATPPDPK1:PIP3:PRKCZMe-PalmS-ESR2 GNG11 AdoHcyESR1 ER alpha46 STRN ESR2 GNAI3 GNG3 CAV1 ATPPalmS-ESR1 p-S10 CDKN1BMe260-ESR1 p-T,Y MAPK dimersADPGNG2 PDPK1 AREG(101-187) Me87-PalmS-ER alpha46 PI(3,4,5)P3 PIK3CA p-T32,S253,S315-FOXO3ER alpha46 ELK1XPO1EGF PI(3,4,5)P3 p-T202,Y204-MAPK3 HSP90AA1 PIK3R3 p-S133-CREB1homodimerESTG:Me260-ESR1dimerPI(3,4,5)P3 GNGT1 RAF/MAP kinasecascadeESTG Me260-ESR1 CALM1 PIK3R2 ESR2 SHC1-1 EPGN(23-154) S-Farn-Me-PalmS KRAS4A p21 RAS:GDPCAV2 PIK3R2 MMP7(95-267) S-Farn-Me KRAS4B pY-PTK2PalmS-ER alpha36 unknownpalmitoyl-(protein)hydrolaseNADP+GNGT2 PDPK1 2xPalmC-MyrG-p-S1177-NOS3 CoA-SHp-Y1161,Y1165,Y1166-IGF1R(741-1367) GNGT1 GNGT1 SPHK1p-T185,Y187-MAPK1 S-Farn-Me-2xPalmS HRAS GNG2 PalmS-ESR1 FMN ESRs:HSBP1 oligomerMe87-PalmS-ER alpha36 ESR1 GNG8 heme GNG4 GNG5 ESTG EREG(60-108) EGF-likeligands:p-6Y EGFRdimer:p-Y397 PTK2PalmS-ER alpha46 PDPK1:PIP3:p-T410-PRKCZEGF-likeligands:p-6Y EGFRdimerGNAI3 ESRs:STRN:ESTG:MyrG-SRCGNB5 PalmS-ESR2 ESTG:ESR1:p-3Y-IGF1R:SHC1ESTG:Me-PalmS-ESRdimersCCND1 geneSHC1ER alpha46 EPGN(23-154) TGFA(24-98) ESTG GNG7 EGF S1PR3 GDP PalmS-ESRs:CAVsESTG ADPADPMe87-PalmS-ER alpha46 PIK3R2 CAV1 GNAT3 GNG3 ESR1 S1P:S1PR3ER alpha36 MyrG-SRCGNAI2 ESTG:ESRs:STRN:heterotrimeric G(i) proteinGNG2 CAV2 GDP GNG5 Me260-ESR1 BTC(32-111) PIK3R1 GNG10 PDPK1 BCL2 genep-S10 CDKN1BPIK3CA PDPK1:PIP3:pS,p-T410 PRKCZAREG(101-187) HBEGF(63-148) ATPESTG L-CitpS, p-T410-PRKCZ ESTG SRFEGF NADPHESR2 GNG12 Me87-PalmS-ER alpha46 MyrG-p-Y419-SRC O2TGFA(24-98) G-protein alpha(i):GDPFAD MyrG-p-Y419-SRC ESTG GNAI2 PRMT1HBEGF(63-148) S-Farn-Me-2xPalmS HRAS MyrG-SRC H2OPalmS-ER alpha36 EGF-likeligands:p-6YEGFR:PTK2Me260-PalmS-ESR1 ER alpha36 PDPK1:PIP3:pS,p-T410 PRKCZ:p21RAS:GTPGNG4 ADPp-T185,Y187 MAPK1dimerSRF p-T309,S474-AKT2 p-4S,T336-ELK1 p-T308,S473-AKT1 Mitotic G1 phase andG1/S transitionESRs:STRN:ESTG:MyrG-pY419-SRCER alpha36 ATPESTGESTG GNAT3 GDP p-Y1161,1165,1166-IGF1RGNG12 Me-PalmS-ESR2 Zn2+ SHC1-1 GNGT2 PIK3R1 GNB4 GNG3 ADPGNB4 p-T185,Y187-MAPK1 GNB4 ATPADPPDPK1:PIP3GNB1 PalmS-ER alpha36 GNG12 UHMK1Ca2+ Signaling by EGFRCAVsHBEGF(20-208)GNB1 Me260-ESR1:STRN:ESTG:MyrG-pY419 SRC:PI3K alphap-S1177-eNOS:CaM:HSP90:p-AKT1:BH4GNB1 CAV1 SHC1-2 MMP2,3,7,9TGFA(24-98) PIK3R3 Metabolism of nitricoxide: NOS3activation andregulationL-ArgGNG10 CCND1 gene:p-S133CREB1 dimerPIK3R2 p-T,p-S-AKTBTC(32-111) ESR1 PDPK1 ESRs:STRN:ESTGNOPDPK1 GNG4 S-Farn-Me PalmS NRAS ATPGNG8 CREB1ER alpha36 GNB3 PALM(-)CDKN1BPIP3 activates AKTsignalingHSBP1 oligomer ER alpha36 HB-EGF(161-208)2, 6-8, 15...5, 70, 136, 1521, 3, 46, 54-56, 88...44, 74, 13159121


Description

In addition to its well-characterized role in estrogen-dependent transcription, estrogen (beta-estradiol, also known as E2) also plays a rapid, non-genomic role through interaction with receptors localized at the plasma membrane by virtue of dynamic palmitoylation. Estrogen receptor palmitoylation is a prerequisite for the E2-dependent activation of extra-nuclear signaling both in vitro and in animal models (Acconcia et al, 2004; Acconcia et al, 2005; Marino et al, 2006; Marino and Ascenzi, 2006). Non-genomic signaling through the estrogen receptor ESR1 also depends on receptor arginine methylation by PMRT1 (Pedram et al, 2007; Pedram et al, 2012; Le Romancer et al, 2008; reviewed in Arnal, 2017; Le Romancer et al, 2011 ).
E2-evoked extra-nuclear signaling is independent of the transcriptional activity of estrogen receptors and occurs within seconds to minutes following E2 administration to target cells. Extra-nuclear signaling consists of the activation of a plethora of signaling pathways including the RAF/MAP kinase cascade and the PI3K/AKT signaling cascade and governs processes such as apoptosis, cellular proliferation and metastasis (reviewed in Hammes et al, 2007; Handa et al, 2012; Lange et al, 2007; Losel et al, 2003; Arnal et al, 2017; Le Romancer et al, 2011). ESR-mediated signaling also cross-talks with receptor tyrosine kinase, NF- kappa beta and GPCR signaling pathways by modulating the post-translational modification of enzymes and other proteins and regulating second messengers (reviewed in Arnal et al, 2017; Schwartz et al, 2016; Boonyaratanakornkit, 2011; Biswas et al, 2005). In the nervous system, E2 affects neural functions such as cognition, behaviour, stress responses and reproduction in part by inducing such rapid extra-nuclear responses (Farach-Carson and Davis, 2003; Losel et al, 2003), while in endothelial cells, non-genomic ESR-dependent signaling also regulates vasodilation through the eNOS pathway (reviewed in Levin, 2011).
Extra-nuclear signaling additionally cross-talks with nuclear estrogen receptor signaling and is required to control ER protein stability (La Rosa et al, 2012)
Recent data have demonstrated that the membrane ESR1 can interact with various endocytic proteins to traffic and signal within the cytoplasm. This receptor intracellular trafficking appears to be dependent on the phyical interaction of ESR1 with specific trans-membrane receptors such as IGR-1R and beta 1-integrin (Sampayo et al, 2018) View original pathway at Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 9009391
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Reactome version: 75
Reactome Author 
Reactome Author: Rothfels, Karen

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  89. Kleinman D, Karas M, Roberts CT, LeRoith D, Phillip M, Segev Y, Levy J, Sharoni Y.; ''Modulation of insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins in endometrial cancer cells by estradiol.''; PubMed Europe PMC Scholia
  90. Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M.; ''S-palmitoylation modulates human estrogen receptor-alpha functions.''; PubMed Europe PMC Scholia
  91. Marino M, Acconcia F, Bresciani F, Weisz A, Trentalance A.; ''Distinct nongenomic signal transduction pathways controlled by 17beta-estradiol regulate DNA synthesis and cyclin D(1) gene transcription in HepG2 cells.''; PubMed Europe PMC Scholia
  92. Zhu X, Bao Y, Guo Y, Yang W.; ''Proline-Rich Protein Tyrosine Kinase 2 in Inflammation and Cancer.''; PubMed Europe PMC Scholia
  93. Kim JH, Kim JH, Song WK, Kim JH, Chun JS.; ''Sphingosine 1-phosphate activates Erk-1/-2 by transactivating epidermal growth factor receptor in rat-2 cells.''; PubMed Europe PMC Scholia
  94. Lösel R, Wehling M.; ''Nongenomic actions of steroid hormones.''; PubMed Europe PMC Scholia
  95. Richards JS, Sharma SC, Falender AE, Lo YH.; ''Expression of FKHR, FKHRL1, and AFX genes in the rodent ovary: evidence for regulation by IGF-I, estrogen, and the gonadotropins.''; PubMed Europe PMC Scholia
  96. Kim KH, Bender JR.; ''Rapid, estrogen receptor-mediated signaling: why is the endothelium so special?''; PubMed Europe PMC Scholia
  97. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  98. Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K, Nakayama KI.; ''Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export.''; PubMed Europe PMC Scholia
  99. Haynes MP, Li L, Sinha D, Russell KS, Hisamoto K, Baron R, Collinge M, Sessa WC, Bender JR.; ''Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen.''; PubMed Europe PMC Scholia
  100. Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH.; ''Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha.''; PubMed Europe PMC Scholia
  101. Cheng M, Sexl V, Sherr CJ, Roussel MF.; ''Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).''; PubMed Europe PMC Scholia
  102. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  103. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  104. Gille H, Kortenjann M, Thomae O, Moomaw C, Slaughter C, Cobb MH, Shaw PE.; ''ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation.''; PubMed Europe PMC Scholia
  105. Castoria G, Migliaccio A, Di Domenico M, Lombardi M, de Falco A, Varricchio L, Bilancio A, Barone MV, Auricchio F.; ''Role of atypical protein kinase C in estradiol-triggered G1/S progression of MCF-7 cells.''; PubMed Europe PMC Scholia
  106. Reynisdóttir I, Massagué J.; ''The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2.''; PubMed Europe PMC Scholia
  107. Kanda N, Watanabe S.; ''17beta-estradiol stimulates the growth of human keratinocytes by inducing cyclin D2 expression.''; PubMed Europe PMC Scholia
  108. Le Romancer M, Poulard C, Cohen P, Sentis S, Renoir JM, Corbo L.; ''Cracking the estrogen receptor's posttranslational code in breast tumors.''; PubMed Europe PMC Scholia
  109. Shaulian E, Karin M.; ''AP-1 as a regulator of cell life and death.''; PubMed Europe PMC Scholia
  110. Ishida N, Kitagawa M, Hatakeyama S, Nakayama K.; ''Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability.''; PubMed Europe PMC Scholia
  111. Marais R, Wynne J, Treisman R.; ''The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain.''; PubMed Europe PMC Scholia
  112. Tanimoto T, Lungu AO, Berk BC.; ''Sphingosine 1-phosphate transactivates the platelet-derived growth factor beta receptor and epidermal growth factor receptor in vascular smooth muscle cells.''; PubMed Europe PMC Scholia
  113. Hammes SR, Levin ER.; ''Minireview: Recent advances in extranuclear steroid receptor actions.''; PubMed Europe PMC Scholia
  114. Albanito L, Sisci D, Aquila S, Brunelli E, Vivacqua A, Madeo A, Lappano R, Pandey DP, Picard D, Mauro L, Andò S, Maggiolini M.; ''Epidermal growth factor induces G protein-coupled receptor 30 expression in estrogen receptor-negative breast cancer cells.''; PubMed Europe PMC Scholia
  115. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  116. Razandi M, Alton G, Pedram A, Ghonshani S, Webb P, Levin ER.; ''Identification of a structural determinant necessary for the localization and function of estrogen receptor alpha at the plasma membrane.''; PubMed Europe PMC Scholia
  117. Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A, Visca P, Marino M.; ''Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol.''; PubMed Europe PMC Scholia
  118. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
  119. Kawada M, Yamagoe S, Murakami Y, Suzuki K, Mizuno S, Uehara Y.; ''Induction of p27Kip1 degradation and anchorage independence by Ras through the MAP kinase signaling pathway.''; PubMed Europe PMC Scholia
  120. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
  121. Le Romancer M, Treilleux I, Leconte N, Robin-Lespinasse Y, Sentis S, Bouchekioua-Bouzaghou K, Goddard S, Gobert-Gosse S, Corbo L.; ''Regulation of estrogen rapid signaling through arginine methylation by PRMT1.''; PubMed Europe PMC Scholia
  122. Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D.; ''The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase.''; PubMed Europe PMC Scholia
  123. Marino M, Ascenzi P.; ''Steroid hormone rapid signaling: the pivotal role of S-palmitoylation.''; PubMed Europe PMC Scholia
  124. Ladikou EE, Kassi E.; ''The emerging role of estrogen in B cell malignancies.''; PubMed Europe PMC Scholia
  125. Bredt DS, Snyder SH.; ''Nitric oxide: a physiologic messenger molecule.''; PubMed Europe PMC Scholia
  126. Song RX, Zhang Z, Chen Y, Bao Y, Santen RJ.; ''Estrogen signaling via a linear pathway involving insulin-like growth factor I receptor, matrix metalloproteinases, and epidermal growth factor receptor to activate mitogen-activated protein kinase in MCF-7 breast cancer cells.''; PubMed Europe PMC Scholia
  127. Burgering BM.; ''A brief introduction to FOXOlogy.''; PubMed Europe PMC Scholia
  128. Castoria G, Giovannelli P, Lombardi M, De Rosa C, Giraldi T, de Falco A, Barone MV, Abbondanza C, Migliaccio A, Auricchio F.; ''Tyrosine phosphorylation of estradiol receptor by Src regulates its hormone-dependent nuclear export and cell cycle progression in breast cancer cells.''; PubMed Europe PMC Scholia
  129. Boonyaratanakornkit V.; ''Scaffolding proteins mediating membrane-initiated extra-nuclear actions of estrogen receptor.''; PubMed Europe PMC Scholia
  130. Levin ER.; ''Integration of the extranuclear and nuclear actions of estrogen.''; PubMed Europe PMC Scholia
  131. Kone BC, Kuncewicz T, Zhang W, Yu ZY.; ''Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide.''; PubMed Europe PMC Scholia
  132. Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K.; ''The retinoblastoma protein binds to a family of E2F transcription factors.''; PubMed Europe PMC Scholia
  133. Wyckoff MH, Chambliss KL, Mineo C, Yuhanna IS, Mendelsohn ME, Mumby SM, Shaul PW.; ''Plasma membrane estrogen receptors are coupled to endothelial nitric-oxide synthase through Galpha(i).''; PubMed Europe PMC Scholia
  134. Hess J, Angel P, Schorpp-Kistner M.; ''AP-1 subunits: quarrel and harmony among siblings.''; PubMed Europe PMC Scholia
  135. Lange CA, Gioeli D, Hammes SR, Marker PC.; ''Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer.''; PubMed Europe PMC Scholia
  136. Carpenter G.; ''Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways.''; PubMed Europe PMC Scholia
  137. Farach-Carson MC, Davis PJ.; ''Steroid hormone interactions with target cells: cross talk between membrane and nuclear pathways.''; PubMed Europe PMC Scholia
  138. Marino M, Acconcia F, Trentalance A.; ''Biphasic estradiol-induced AKT phosphorylation is modulated by PTEN via MAP kinase in HepG2 cells.''; PubMed Europe PMC Scholia
  139. Ariazi EA, Brailoiu E, Yerrum S, Shupp HA, Slifker MJ, Cunliffe HE, Black MA, Donato AL, Arterburn JB, Oprea TI, Prossnitz ER, Dun NJ, Jordan VC.; ''The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells.''; PubMed Europe PMC Scholia
  140. Pedram A, Razandi M, Deschenes RJ, Levin ER.; ''DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors.''; PubMed Europe PMC Scholia
  141. Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER.; ''A conserved mechanism for steroid receptor translocation to the plasma membrane.''; PubMed Europe PMC Scholia
  142. Tuteja N, Chandra M, Tuteja R, Misra MK.; ''Nitric Oxide as a Unique Bioactive Signaling Messenger in Physiology and Pathophysiology.''; PubMed Europe PMC Scholia
  143. Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, Schlaepfer DD.; ''FAK integrates growth-factor and integrin signals to promote cell migration.''; PubMed Europe PMC Scholia
  144. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME.; ''Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.''; PubMed Europe PMC Scholia
  145. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM.; ''Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN.''; PubMed Europe PMC Scholia
  146. Sato K, Nagao T, Kakumoto M, Kimoto M, Otsuki T, Iwasaki T, Tokmakov AA, Owada K, Fukami Y.; ''Adaptor protein Shc is an isoform-specific direct activator of the tyrosine kinase c-Src.''; PubMed Europe PMC Scholia
  147. Liu M, Yang Y, Wang C, Sun L, Mei C, Yao W, Liu Y, Shi Y, Qiu S, Fan J, Cai X, Zha X.; ''The effect of epidermal growth factor receptor variant III on glioma cell migration by stimulating ERK phosphorylation through the focal adhesion kinase signaling pathway.''; PubMed Europe PMC Scholia
  148. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC Scholia
  149. Park YG, Park S, Lim SO, Lee MS, Ryu CK, Kim I, Cho-Chung YS.; ''Reduction in cyclin D1/Cdk4/retinoblastoma protein signaling by CRE-decoy oligonucleotide.''; PubMed Europe PMC Scholia
  150. Yune TY, Park HG, Lee JY, Oh TH.; ''Estrogen-induced Bcl-2 expression after spinal cord injury is mediated through phosphoinositide-3-kinase/Akt-dependent CREB activation.''; PubMed Europe PMC Scholia
  151. Aktas H, Cai H, Cooper GM.; ''Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1.''; PubMed Europe PMC Scholia
  152. Schlessinger J.; ''Ligand-induced, receptor-mediated dimerization and activation of EGF receptor.''; PubMed Europe PMC Scholia
  153. Yu WH, Woessner JF, McNeish JD, Stamenkovic I.; ''CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling.''; PubMed Europe PMC Scholia
  154. Lin BC, Suzawa M, Blind RD, Tobias SC, Bulun SE, Scanlan TS, Ingraham HA.; ''Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation.''; PubMed Europe PMC Scholia
  155. Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, Nuckolls F, Giangrande P, Wright FA, Field SJ, Greenberg ME, Orkin S, Nevins JR, Robinson ML, Leone G.; ''The E2F1-3 transcription factors are essential for cellular proliferation.''; PubMed Europe PMC Scholia
  156. Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E, Auricchio F.; ''Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells.''; PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
114705view16:18, 25 January 2021ReactomeTeamReactome version 75
113150view11:21, 2 November 2020ReactomeTeamReactome version 74
112788view17:44, 9 October 2020DeSlOntology Term : 'estrogen signaling pathway' added !
112743view16:14, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xPalmC-MyrG-p-S1177-NOS3 ProteinP29474 (Uniprot-TrEMBL)
ADMAMetaboliteCHEBI:25682 (ChEBI)
ADPMetaboliteCHEBI:456216 (ChEBI)
AREG(101-187) ProteinP15514 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
BCL2 geneGeneProductENSG00000171791 (Ensembl)
BCL2ProteinP10415 (Uniprot-TrEMBL)
BH4 MetaboliteCHEBI:15372 (ChEBI)
BTC(32-111) ProteinP35070 (Uniprot-TrEMBL)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CAV1 ProteinQ03135 (Uniprot-TrEMBL)
CAV2 ProteinP51636 (Uniprot-TrEMBL)
CAVsComplexR-HSA-9021039 (Reactome)
CAVsComplexR-HSA-9021041 (Reactome)
CCND1 gene ProteinENSG00000110092 (Ensembl)
CCND1 gene:p-S133 CREB1 dimerComplexR-HSA-9623342 (Reactome)
CCND1 geneGeneProductENSG00000110092 (Ensembl)
CCND1ProteinP24385 (Uniprot-TrEMBL)
CDKN1BProteinP46527 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
EGF ProteinP01133 (Uniprot-TrEMBL)
EGF-like

ligands:p-6Y

EGFR:PTK2
ComplexR-HSA-9625453 (Reactome)
EGF-like

ligands:p-6Y EGFR

dimer:p-Y397 PTK2
ComplexR-HSA-9625464 (Reactome)
EGF-like

ligands:p-6Y EGFR

dimer
ComplexR-HSA-9624425 (Reactome)
ELK1ProteinP19419 (Uniprot-TrEMBL)
EPGN(23-154) ProteinQ6UW88 (Uniprot-TrEMBL)
ER alpha36 ProteinP03372-4 (Uniprot-TrEMBL)
ER alpha46 ProteinP03372-3 (Uniprot-TrEMBL)
EREG(60-108) ProteinO14944 (Uniprot-TrEMBL)
ESR1 ProteinP03372 (Uniprot-TrEMBL)
ESR2 ProteinQ92731 (Uniprot-TrEMBL)
ESRs:HSBP1 oligomerComplexR-HSA-9021048 (Reactome)
ESRs:STRN:ESTG:MyrG-SRCComplexR-HSA-9021587 (Reactome)
ESRs:STRN:ESTG:MyrG-pY419 SRC:PI3K alphaComplexR-HSA-9021654 (Reactome)
ESRs:STRN:ESTG:MyrG-pY419-SRCComplexR-HSA-9021593 (Reactome)
ESRs:STRN:ESTGComplexR-HSA-9027648 (Reactome)
ESTG MetaboliteCHEBI:50114 (ChEBI)
ESTG:ESR1:p-3Y-IGF1R:SHC1ComplexR-HSA-9634580 (Reactome)
ESTG:ESRs:STRN:heterotrimeric G(i) proteinComplexR-HSA-9021595 (Reactome)
ESTG:Me-PalmS-ESR dimersComplexR-HSA-9634612 (Reactome)
ESTG:Me260-ESR1 dimerComplexR-HSA-9634581 (Reactome)
ESTGMetaboliteCHEBI:50114 (ChEBI)
FAD MetaboliteCHEBI:16238 (ChEBI)
FMN MetaboliteCHEBI:17621 (ChEBI)
FOS

gene:SRF:p-4S,T336

ELK1
ComplexR-HSA-9625460 (Reactome)
FOS gene ProteinENSG00000170345 (Ensembl)
FOS geneGeneProductENSG00000170345 (Ensembl)
FOSProteinP01100 (Uniprot-TrEMBL)
FOXO3ProteinO43524 (Uniprot-TrEMBL)
G-protein alpha (i):GDPComplexR-HSA-392164 (Reactome)
G-protein beta-gamma complexComplexR-HSA-167434 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GNAI1 ProteinP63096 (Uniprot-TrEMBL)
GNAI2 ProteinP04899 (Uniprot-TrEMBL)
GNAI3 ProteinP08754 (Uniprot-TrEMBL)
GNAT3 ProteinA8MTJ3 (Uniprot-TrEMBL)
GNB1 ProteinP62873 (Uniprot-TrEMBL)
GNB2 ProteinP62879 (Uniprot-TrEMBL)
GNB3 ProteinP16520 (Uniprot-TrEMBL)
GNB4 ProteinQ9HAV0 (Uniprot-TrEMBL)
GNB5 ProteinO14775 (Uniprot-TrEMBL)
GNG10 ProteinP50151 (Uniprot-TrEMBL)
GNG11 ProteinP61952 (Uniprot-TrEMBL)
GNG12 ProteinQ9UBI6 (Uniprot-TrEMBL)
GNG13 ProteinQ9P2W3 (Uniprot-TrEMBL)
GNG2 ProteinP59768 (Uniprot-TrEMBL)
GNG3 ProteinP63215 (Uniprot-TrEMBL)
GNG4 ProteinP50150 (Uniprot-TrEMBL)
GNG5 ProteinP63218 (Uniprot-TrEMBL)
GNG7 ProteinO60262 (Uniprot-TrEMBL)
GNG8 ProteinQ9UK08 (Uniprot-TrEMBL)
GNGT1 ProteinP63211 (Uniprot-TrEMBL)
GNGT2 ProteinO14610 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HB-EGF(161-208)ProteinQ99075 (Uniprot-TrEMBL)
HBEGF(20-208)ProteinQ99075 (Uniprot-TrEMBL)
HBEGF(63-148) ProteinQ99075 (Uniprot-TrEMBL)
HBEGF(63-148)ProteinQ99075 (Uniprot-TrEMBL)
HSBP1 oligomer R-HSA-5218689 (Reactome)
HSBP1 oligomerR-HSA-5218689 (Reactome)
HSP90AA1 ProteinP07900 (Uniprot-TrEMBL)
Heterotrimeric

G-protein Gi

(inactive)
ComplexR-HSA-392165 (Reactome)
IGF1R(31-736) ProteinP08069 (Uniprot-TrEMBL)
L-ArgMetaboliteCHEBI:32682 (ChEBI)
L-CitMetaboliteCHEBI:16349 (ChEBI)
MMP2(110-660) ProteinP08253 (Uniprot-TrEMBL)
MMP2,3,7,9ComplexR-HSA-9624267 (Reactome)
MMP3(100-477) ProteinP08254 (Uniprot-TrEMBL)
MMP7(95-267) ProteinP09237 (Uniprot-TrEMBL)
MMP9(107-707) ProteinP14780 (Uniprot-TrEMBL)
Me-PalmS-ESR2 ProteinQ92731 (Uniprot-TrEMBL)
Me-PalmS-ESRsComplexR-HSA-9637789 (Reactome)
Me260-ESR1 ProteinP03372 (Uniprot-TrEMBL)
Me260-ESR1:STRN:ESTG: MyrG-pY419 SRC:PI3Kalpha:pY-PTK2ComplexR-HSA-9632407 (Reactome)
Me260-ESR1:STRN:ESTG:MyrG-pY419 SRC:PI3K alphaComplexR-HSA-9632399 (Reactome)
Me260-PalmS-ESR1 ProteinP03372 (Uniprot-TrEMBL)
Me87-PalmS-ER alpha36 ProteinP03372-4 (Uniprot-TrEMBL)
Me87-PalmS-ER alpha46 ProteinP03372-3 (Uniprot-TrEMBL)
Metabolism of nitric

oxide: NOS3 activation and

regulation
PathwayR-HSA-202131 (Reactome) Nitric oxide (NO), a multifunctional second messenger, is implicated in physiological processes in mammals that range from immune response and potentiation of synaptic transmission to dilation of blood vessels and muscle relaxation. NO is a highly active molecule that diffuses across cell membranes and cannot be stored inside the producing cell. Its signaling capacity is controlled at the levels of biosynthesis and local availability. Its production by NO synthases is under complex and tight control, being regulated at transcriptional and translational levels, through co- and posttranslational modifications, and by subcellular localization. NO is synthesized from L-arginine by a family of nitric oxide synthases (NOS). Three NOS isoforms have been characterized: neuronal NOS (nNOS, NOS1) primarily found in neuronal tissue and skeletal muscle; inducible NOS (iNOS, NOS2) originally isolated from macrophages and later discovered in many other cell types; and endothelial NOS (eNOS, NOS3) present in vascular endothelial cells, cardiac myocytes, and in blood platelets. The enzymatic activity of all three isoforms is dependent on calmodulin, which binds to nNOS and eNOS at elevated intracellular calcium levels, while it is tightly associated with iNOS even at basal calcium levels. As a result, the enzymatic activity of nNOS and eNOS is modulated by changes in intracellular calcium levels, leading to transient NO production, while iNOS continuously releases NO independent of fluctuations in intracellular calcium levels and is mainly regulated at the gene expression level (Pacher et al. 2007).

The NOS enzymes share a common basic structural organization and requirement for substrate cofactors for enzymatic activity. A central calmodulin-binding motif separates an NH2-terminal oxygenase domain from a COOH-terminal reductase domain. Binding sites for cofactors NADPH, FAD, and FMN are located within the reductase domain, while binding sites for tetrahydrobiopterin (BH4) and heme are located within the oxygenase domain. Once calmodulin binds, it facilitates electron transfer from the cofactors in the reductase domain to heme enabling nitric oxide production. Both nNOS and eNOS contain an additional insert (40-50 amino acids) in the middle of the FMN-binding subdomain that serves as autoinhibitory loop, destabilizing calmodulin binding at low calcium levels and inhibiting electron transfer from FMN to the heme in the absence of calmodulin. iNOS does not contain this insert.

In this Reactome pathway module, details of eNOS activation and regulation are annotated. Originally identified as endothelium-derived relaxing factor, eNOS derived NO is a critical signaling molecule in vascular homeostasis. It regulates blood pressure and vascular tone, and is involved in vascular smooth muscle cell proliferation, platelet aggregation, and leukocyte adhesion. Loss of endothelium derived NO is a key feature of endothelial dysfunction, implicated in the pathogenesis of hypertension and atherosclerosis. The endothelial isoform eNOS is unique among the nitric oxide synthase (NOS) family in that it is co-translationally modified at its amino terminus by myristoylation and is further acylated by palmitoylation (two residues next to the myristoylation site). These modifications target eNOS to the plasma membrane caveolae and lipid rafts.

Factors that stimulate eNOS activation and nitric oxide (NO) production include fluid shear stress generated by blood flow, vascular endothelial growth factor (VEGF), bradykinin, estrogen, insulin, and angiopoietin. The activity of eNOS is further regulated by numerous post-translational modifications, including protein-protein interactions, phosphorylation, and subcellular localization.

Following activation, eNOS shuttles between caveolae and other subcellular compartments such as the noncaveolar plasma membrane portions, Golgi apparatus, and perinuclear structures. This subcellular distribution is variable depending upon cell type and mode of activation.

Subcellular localization of eNOS has a profound effect on its ability to produce NO as the availability of its substrates and cofactors will vary with location. eNOS is primarily particulate, and depending on the cell type, eNOS can be found in several membrane compartments: plasma membrane caveolae, lipid rafts, and intracellular membranes such as the Golgi complex.

Mitotic G1 phase and G1/S transitionPathwayR-HSA-453279 (Reactome) Mitotic G1-G1/S phase involves G1 phase of the mitotic interphase and G1/S transition, when a cell commits to DNA replication and divison genetic and cellular material to two daughter cells.

During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).

During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.

MyrG-SRC ProteinP12931 (Uniprot-TrEMBL)
MyrG-SRCProteinP12931 (Uniprot-TrEMBL)
MyrG-p-Y419-SRC ProteinP12931 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NOMetaboliteCHEBI:16480 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PALM(-)MetaboliteCHEBI:7896 (ChEBI)
PALM-CoAMetaboliteCHEBI:15525 (ChEBI)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1:PIP3:PRKCZComplexR-HSA-437191 (Reactome)
PDPK1:PIP3:p-T410-PRKCZComplexR-HSA-437184 (Reactome)
PDPK1:PIP3:pS,

p-T410 PRKCZ:p21

RAS:GDP
ComplexR-HSA-9632908 (Reactome)
PDPK1:PIP3:pS,

p-T410 PRKCZ:p21

RAS:GTP
ComplexR-HSA-9632904 (Reactome)
PDPK1:PIP3:pS, p-T410 PRKCZComplexR-HSA-9632853 (Reactome)
PDPK1:PIP3ComplexR-HSA-377179 (Reactome)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI3K alphaComplexR-HSA-198379 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PRKCZ ProteinQ05513 (Uniprot-TrEMBL)
PRKCZProteinQ05513 (Uniprot-TrEMBL)
PRMT1ProteinQ99873 (Uniprot-TrEMBL)
PTK2 ProteinQ05397 (Uniprot-TrEMBL)
PTK2ProteinQ05397 (Uniprot-TrEMBL)
PalmS-ER alpha36 ProteinP03372-4 (Uniprot-TrEMBL)
PalmS-ER alpha46 ProteinP03372-3 (Uniprot-TrEMBL)
PalmS-ESR1 ProteinP03372 (Uniprot-TrEMBL)
PalmS-ESR2 ProteinQ92731 (Uniprot-TrEMBL)
PalmS-ESRs:CAVsComplexR-HSA-9021067 (Reactome)
PalmS-ESRs:STRN:ESTGComplexR-HSA-9021165 (Reactome)
PalmS-ESRsComplexR-HSA-9021061 (Reactome)
PalmS-ESRsComplexR-HSA-9021065 (Reactome)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
S-Farn-Me KRAS4B ProteinP01116-2 (Uniprot-TrEMBL)
S-Farn-Me PalmS NRAS ProteinP01111 (Uniprot-TrEMBL)
S-Farn-Me-2xPalmS HRAS ProteinP01112 (Uniprot-TrEMBL)
S-Farn-Me-PalmS KRAS4A ProteinP01116-1 (Uniprot-TrEMBL)
S1P MetaboliteCHEBI:37550 (ChEBI)
S1P:S1PR3ComplexR-HSA-9625811 (Reactome)
S1PMetaboliteCHEBI:37550 (ChEBI)
S1PR3 ProteinQ99500 (Uniprot-TrEMBL)
S1PR3ProteinQ99500 (Uniprot-TrEMBL)
SHC1-1 ProteinP29353-1 (Uniprot-TrEMBL)
SHC1-2 ProteinP29353-2 (Uniprot-TrEMBL)
SHC1-3 ProteinP29353-3 (Uniprot-TrEMBL)
SHC1ComplexR-HSA-9623997 (Reactome)
SPGMetaboliteCHEBI:16393 (ChEBI)
SPHK1ProteinQ9NYA1 (Uniprot-TrEMBL)
SRF ProteinP11831 (Uniprot-TrEMBL)
SRFProteinP11831 (Uniprot-TrEMBL)
STRN ProteinO43815 (Uniprot-TrEMBL)
STRNProteinO43815 (Uniprot-TrEMBL)
Signaling by EGFRPathwayR-HSA-177929 (Reactome) The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor. Phosphorylated tyrosines serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, which then stimulate intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival. Recruitment of complexes containing GRB2 and SOS1 to phosphorylated EGFR dimers either directly, through phosphotyrosine residues that serve as GRB2 docking sites, or indirectly, through SHC1 recruitment, promotes GDP to GTP exchange on RAS, resulting in the activation of RAF/MAP kinase cascade. Binding of complexes of GRB2 and GAB1 to phosphorylated EGFR dimers leads to formation of the active PI3K complex, conversion of PIP2 into PIP3, and activation of AKT signaling. Phospholipase C-gamma1 (PLCG1) can also be recruited directly, through EGFR phosphotyrosine residues that serve as PLCG1 docking sites, which leads to PLCG1 phosphorylation by EGFR and activation of DAG and IP3 signaling. EGFR signaling is downregulated by the action of ubiquitin ligase CBL. CBL binds directly to the phosphorylated EGFR dimer through the phosphotyrosine Y1045 in the C-tail of EGFR, and after CBL is phosphorylated by EGFR, it becomes active and ubiquitinates phosphorylated EGFR dimers, targeting them for degradation. For a recent review of EGFR signaling, please refer to Avraham and Yarden, 2011.
TGFA(24-98) ProteinP01135 (Uniprot-TrEMBL)
UHMK1ProteinQ8TAS1 (Uniprot-TrEMBL)
XPO1ProteinO14980 (Uniprot-TrEMBL)
ZDHHC21 ProteinQ8IVQ6 (Uniprot-TrEMBL)
ZDHHC7 ProteinQ9NXF8 (Uniprot-TrEMBL)
ZDHHC7, ZDHHC21ComplexR-HSA-9021070 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
heme MetaboliteCHEBI:17627 (ChEBI)
p-4S,T336-ELK1 ProteinP19419 (Uniprot-TrEMBL)
p-4S,T336-ELK1ProteinP19419 (Uniprot-TrEMBL)
p-6Y-EGFR ProteinP00533 (Uniprot-TrEMBL)
p-S10 CDKN1BProteinP46527 (Uniprot-TrEMBL)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4ComplexR-HSA-1497830 (Reactome)
p-S133-CREB1 homodimerComplexR-HSA-111911 (Reactome)
p-S133-CREB1 ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-T,Y MAPK dimersComplexR-HSA-198701 (Reactome)
p-T,p-S-AKTComplexR-HSA-202072 (Reactome)
p-T185,Y187 MAPK1 dimerComplexR-HSA-109855 (Reactome)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T32,S253,S315-FOXO3ProteinO43524 (Uniprot-TrEMBL)
p-T410-PRKCZ ProteinQ05513 (Uniprot-TrEMBL)
p-Y1161,1165,1166-IGF1RComplexR-HSA-2404188 (Reactome)
p-Y1161,Y1165,Y1166-IGF1R(741-1367) ProteinP08069 (Uniprot-TrEMBL)
p-Y185,Y187 MAPK1 dimerComplexR-HSA-109856 (Reactome)
p-Y397-PTK2 ProteinQ05397 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
pS, p-T410-PRKCZ ProteinQ05513 (Uniprot-TrEMBL)
pY-PTK2 ProteinQ05397 (Uniprot-TrEMBL)
pY-PTK2ProteinQ05397 (Uniprot-TrEMBL)
unknown

palmitoyl-(protein)

hydrolase
R-HSA-9027665 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADMATBarR-HSA-202127 (Reactome)
ADPArrowR-HSA-198731 (Reactome)
ADPArrowR-HSA-199298 (Reactome)
ADPArrowR-HSA-437195 (Reactome)
ADPArrowR-HSA-9021609 (Reactome)
ADPArrowR-HSA-9624526 (Reactome)
ADPArrowR-HSA-9625487 (Reactome)
ADPArrowR-HSA-9632858 (Reactome)
ADPArrowR-HSA-9632868 (Reactome)
ATPR-HSA-198731 (Reactome)
ATPR-HSA-199298 (Reactome)
ATPR-HSA-437195 (Reactome)
ATPR-HSA-9021609 (Reactome)
ATPR-HSA-9624526 (Reactome)
ATPR-HSA-9625487 (Reactome)
ATPR-HSA-9632858 (Reactome)
ATPR-HSA-9632868 (Reactome)
AdoHcyArrowR-HSA-9632182 (Reactome)
AdoMetR-HSA-9632182 (Reactome)
BCL2 geneR-HSA-9623999 (Reactome)
BCL2ArrowR-HSA-9623999 (Reactome)
CAVsArrowR-HSA-9021079 (Reactome)
CAVsR-HSA-9021068 (Reactome)
CCND1 gene:p-S133 CREB1 dimerArrowR-HSA-9623341 (Reactome)
CCND1 gene:p-S133 CREB1 dimerArrowR-HSA-9623355 (Reactome)
CCND1 geneR-HSA-9623341 (Reactome)
CCND1 geneR-HSA-9623355 (Reactome)
CCND1ArrowR-HSA-9623355 (Reactome)
CDKN1BR-HSA-9632868 (Reactome)
CREB1R-HSA-199298 (Reactome)
CoA-SHArrowR-HSA-9021072 (Reactome)
EGF-like

ligands:p-6Y

EGFR:PTK2
ArrowR-HSA-9625482 (Reactome)
EGF-like

ligands:p-6Y

EGFR:PTK2
R-HSA-9625487 (Reactome)
EGF-like

ligands:p-6Y

EGFR:PTK2
mim-catalysisR-HSA-9625487 (Reactome)
EGF-like

ligands:p-6Y EGFR

dimer:p-Y397 PTK2
ArrowR-HSA-9625465 (Reactome)
EGF-like

ligands:p-6Y EGFR

dimer:p-Y397 PTK2
ArrowR-HSA-9625487 (Reactome)
EGF-like

ligands:p-6Y EGFR

dimer
R-HSA-9625482 (Reactome)
ELK1R-HSA-198731 (Reactome)
ESRs:HSBP1 oligomerR-HSA-9021072 (Reactome)
ESRs:STRN:ESTG:MyrG-SRCArrowR-HSA-9021596 (Reactome)
ESRs:STRN:ESTG:MyrG-SRCR-HSA-9021609 (Reactome)
ESRs:STRN:ESTG:MyrG-SRCmim-catalysisR-HSA-9021609 (Reactome)
ESRs:STRN:ESTG:MyrG-pY419 SRC:PI3K alphaArrowR-HSA-9021660 (Reactome)
ESRs:STRN:ESTG:MyrG-pY419-SRCArrowR-HSA-9021609 (Reactome)
ESRs:STRN:ESTG:MyrG-pY419-SRCR-HSA-9021660 (Reactome)
ESRs:STRN:ESTGArrowR-HSA-9021600 (Reactome)
ESRs:STRN:ESTGArrowR-HSA-9027670 (Reactome)
ESRs:STRN:ESTGR-HSA-9021596 (Reactome)
ESRs:STRN:ESTGR-HSA-9021601 (Reactome)
ESTG:ESR1:p-3Y-IGF1R:SHC1ArrowR-HSA-9624272 (Reactome)
ESTG:ESR1:p-3Y-IGF1R:SHC1ArrowR-HSA-9634584 (Reactome)
ESTG:ESRs:STRN:heterotrimeric G(i) proteinArrowR-HSA-9021601 (Reactome)
ESTG:ESRs:STRN:heterotrimeric G(i) proteinR-HSA-9021600 (Reactome)
ESTG:Me-PalmS-ESR dimersArrowR-HSA-9021170 (Reactome)
ESTG:Me-PalmS-ESR dimersR-HSA-9633044 (Reactome)
ESTG:Me260-ESR1 dimerArrowR-HSA-9625814 (Reactome)
ESTG:Me260-ESR1 dimerR-HSA-9634584 (Reactome)
ESTGArrowR-HSA-9632182 (Reactome)
ESTGR-HSA-9021170 (Reactome)
FOS

gene:SRF:p-4S,T336

ELK1
ArrowR-HSA-9625465 (Reactome)
FOS

gene:SRF:p-4S,T336

ELK1
ArrowR-HSA-9625479 (Reactome)
FOS geneR-HSA-9625465 (Reactome)
FOS geneR-HSA-9625479 (Reactome)
FOSArrowR-HSA-9625465 (Reactome)
FOXO3R-HSA-9624526 (Reactome)
G-protein alpha (i):GDPArrowR-HSA-9021596 (Reactome)
G-protein alpha (i):GDPArrowR-HSA-9021600 (Reactome)
G-protein beta-gamma complexArrowR-HSA-9021596 (Reactome)
G-protein beta-gamma complexArrowR-HSA-9021600 (Reactome)
H2OR-HSA-9027670 (Reactome)
HB-EGF(161-208)ArrowR-HSA-9624272 (Reactome)
HBEGF(20-208)R-HSA-9624272 (Reactome)
HBEGF(63-148)ArrowR-HSA-9624272 (Reactome)
HSBP1 oligomerArrowR-HSA-9021072 (Reactome)
Heterotrimeric

G-protein Gi

(inactive)
R-HSA-9021601 (Reactome)
L-ArgR-HSA-202127 (Reactome)
L-CitArrowR-HSA-202127 (Reactome)
MMP2,3,7,9mim-catalysisR-HSA-9624272 (Reactome)
Me-PalmS-ESRsArrowR-HSA-9632182 (Reactome)
Me-PalmS-ESRsR-HSA-9021170 (Reactome)
Me260-ESR1:STRN:ESTG: MyrG-pY419 SRC:PI3Kalpha:pY-PTK2ArrowR-HSA-9632412 (Reactome)
Me260-ESR1:STRN:ESTG:MyrG-pY419 SRC:PI3K alphaR-HSA-9632412 (Reactome)
MyrG-SRCR-HSA-9021596 (Reactome)
NADP+ArrowR-HSA-202127 (Reactome)
NADPHR-HSA-202127 (Reactome)
NOArrowR-HSA-202127 (Reactome)
O2R-HSA-202127 (Reactome)
PALM(-)ArrowR-HSA-9027670 (Reactome)
PALM-CoAR-HSA-9021072 (Reactome)
PDPK1:PIP3:PRKCZArrowR-HSA-437192 (Reactome)
PDPK1:PIP3:PRKCZR-HSA-437195 (Reactome)
PDPK1:PIP3:PRKCZmim-catalysisR-HSA-437195 (Reactome)
PDPK1:PIP3:p-T410-PRKCZArrowR-HSA-437195 (Reactome)
PDPK1:PIP3:p-T410-PRKCZR-HSA-9632858 (Reactome)
PDPK1:PIP3:p-T410-PRKCZmim-catalysisR-HSA-9632858 (Reactome)
PDPK1:PIP3:pS,

p-T410 PRKCZ:p21

RAS:GDP
ArrowR-HSA-9632906 (Reactome)
PDPK1:PIP3:pS,

p-T410 PRKCZ:p21

RAS:GDP
R-HSA-9632918 (Reactome)
PDPK1:PIP3:pS,

p-T410 PRKCZ:p21

RAS:GTP
ArrowR-HSA-9632910 (Reactome)
PDPK1:PIP3:pS,

p-T410 PRKCZ:p21

RAS:GTP
ArrowR-HSA-9632918 (Reactome)
PDPK1:PIP3:pS, p-T410 PRKCZArrowR-HSA-9632858 (Reactome)
PDPK1:PIP3:pS, p-T410 PRKCZR-HSA-9632906 (Reactome)
PDPK1:PIP3R-HSA-437192 (Reactome)
PI3K alphaR-HSA-9021660 (Reactome)
PRKCZR-HSA-437192 (Reactome)
PRMT1mim-catalysisR-HSA-9632182 (Reactome)
PTK2R-HSA-9625482 (Reactome)
PalmS-ESRs:CAVsArrowR-HSA-9021068 (Reactome)
PalmS-ESRs:CAVsR-HSA-9021079 (Reactome)
PalmS-ESRs:STRN:ESTGArrowR-HSA-9633044 (Reactome)
PalmS-ESRs:STRN:ESTGR-HSA-9027670 (Reactome)
PalmS-ESRsArrowR-HSA-9021072 (Reactome)
PalmS-ESRsArrowR-HSA-9021079 (Reactome)
PalmS-ESRsR-HSA-9021068 (Reactome)
PalmS-ESRsR-HSA-9632182 (Reactome)
R-HSA-111916 (Reactome) Based on studies in rat cells, activation of CREB1 by phosphorylation at serine residue S133 induces formation of CREB1 homodimers which are able to bind DNA (Yamamoto et al. 1988). The DNA binding and dimerization domains reside in the C-terminal region of CREB1 (Yun et al. 1990).
R-HSA-198731 (Reactome) Following translocation to the nucleus, ERK1/2 directly phosphorylates key effectors, including the ubiquitous transcription factors ELK1 (Ets like protein 1). At least five residues in the C terminal domain of ELK1 are phosphorylated upon stimulation with growth factor stimulation. ELK1 can form a ternary complex with the serum response factor (SRF) and consensus sequences, such as serum response elements (SRE), on DNA, thus stimulating transcription of a set of immediate early genes like FOS (c-fos) (Marais et al, 1993; Gille et al, 1995; Duan et al, 1998; reviewed in Treisman, 1995).
R-HSA-199298 (Reactome) AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival.
R-HSA-202127 (Reactome) Nitric oxide (NO) is produced from L-arginine by the family of nitric oxide synthases (NOS) enzymes, forming the free radical NO and citrulline as byproduct. The cofactor tetrahydrobiopterin (BH4) is an essential requirement for the delivery of an electron to the intermediate in the catalytic cycle of NOS.
R-HSA-437192 (Reactome) 3-phosphoinositide dependent protein kinase-1 (PDPK1, also known as PDK1) and Protein kinase C zeta type (PRKCZ, also known as PKC zeta) are associated in fibroblasts.
R-HSA-437195 (Reactome) 3-phosphoinositide dependent protein kinase-1 (Pdpk1, also known as Pdk1 and PKB kinase because of its activity at Protein kinase B) phosphorylates T410 of protein kinase C zeta type (Prkcz, also known as PKC zeta), leading to activation. The motif surrounding T410 is highly conserved in other PKC family members suggesting that Pdpk1 might activate other PKCs.
R-HSA-9021068 (Reactome) Palmitoylated estrogen receptors bind caveolin proteins (CAVs) prior to translocation to the plasma membrane (Razandi et al, 2002; Acconcia et al, 2004; Acconcia et al, 2005; Pedram et al, 2007; Pedram et al, 2012). Membrane localization depends on the scaffolding domain (aa 80- 100) of caveolin, although this region is dispensable for estrogen receptor binding (Razandi et al, 2002; Pedram et al, 2007). Interaction between caveolin and the estrogen receptor is diminished upon stimulation of cells with E2 (beta-estradiol) in some cell types, which may restrict the duration of the immediate signaling (Acconcia et al, 2004; Acconcia et al, 2005).
R-HSA-9021072 (Reactome) In addition to nuclear signaling, estrogen receptors also promote a rapid, transcription- and translation-independent signaling response from the plasma membrane (reviewed in Levin, 2005; Schwartz et al, 2016). In contrast to their classical nuclear counterparts, estrogen receptors that signal from the plasma membrane are lipid-modified by palmitoylation. The amino-acid sequence encompassing an exposed cysteine residue (Cys447 for ESR1 and Cys399 for ESR2) is conserved between other steroid hormone receptors (Marino and Ascenzi, 2006). Mutation of the target cysteine in this motif abrogates membrane localization and the rapid response to estrogen (Acconcia et al, 2004; Acconcia et al, 2005; Pedram et al, 2007; Pedram et al, 2011). Golgi-localized palmitoyltransferases ZDHHC7 and ZDHHC21 catalyze the transfer of palmitoyl to the cysteine residue in the estrogen receptor (Pedram et al, 2012).
R-HSA-9021079 (Reactome) Palmitoylation of estrogen receptors promotes their interaction with caveolin (CAV), which is required for their translocation to the plasma membrane where they function in rapid, transcription-independent signaling (Chambliss et al, 2002; Razandi et al, 2003; Acconcia et al, 2004; Pedram et al, 2007; Razandi et al, 2010; Pedram et al, 2012; reviewed in Schwartz et al, 2016). Approximately 5-15% of total cellular estrogen receptor is at the plasma membrane where it is enriched in caveolae (Pedram et al, 2006; Marino et al, 2006).
R-HSA-9021170 (Reactome) Plasma membrane-localized estrogen receptors signal as dimers, and dimerization is promoted by stimulation with estrogen (Razandi et al, 2004). Because palmitoylation of cytoplasmic estrogen receptors occurs on the monomeric form, estrogen (ESTG) stimulation restricts both the amount of palmitoylated receptor and its localization at the plasma membrane (Acconcia et al, 2005; Razandi et al, 2010; Pedram et al, 2012). This may serve to limit the extent of the rapid response to estrogen stimulation.
R-HSA-9021596 (Reactome) Rapid signaling downstream of estrogen stimulation activates signaling through MAP kinase and PI3K/AKT signaling pathways, as well as initiating cross-talk with NF kappa beta and receptor tyrosine kinase pathways (reviewed in Hammes et al, 2007; Handa et al, 2012; Lange et al, 2017; Losel et al, 2003). Signaling through AKT regulates cell cycle progression through CREB-mediated upregulation of cyclin D1 and depends on recruitment of SRC and the p85 regulatory subunit of PI3K (Castoria et al, 2001; Marino et al, 2002; Marino et al, 2003; Castoria et al, 2012; reviewed in Castoria et al, 2010). Estrogen-stimulated nitric oxide (NO) release from endothelial cells likewise depends on the recruitment of SRC to the estrogen receptors at the plasma membrane (Haynes et al, 2003).
Once recruited, SRC is activated by autophosphorylation at tyrosine 419, which in turn is required for the recruitment and activation of PI3K and AKT, and ultimately for the activation of endothelial nitric oxide synthase (eNOS) and promotion of AKT-dependent cellular proliferation (Haynes et al, 2000; Simoncini et al, 2000; Haynes et al, 2003; Li et al, 2007; reviewed in Kim and Bender, 2005; Hammes and Levin, 2011; Le Romancer et al, 2011: Castoria et al, 2010). Formation of an eNOS signaling complex also depends on interaction between the estrogen receptor and heterotrimeric G-proteins (Wyckoff et al, 2001; reviewed in Schwartz, 2016).
R-HSA-9021600 (Reactome) Estrogen-stimulation promotes dissociation of the G protein subunits and stimulates downstream signaling through SRC and PI3K (Castoria et al, 2001; Castoria et al, 2012; Wyckoff et al, 2001).
R-HSA-9021601 (Reactome) Plasma-membrane localized estrogen receptors interact with and signal through heterotrimeric G-proteins (Wyckoff et al, 2001). The estrogen receptor makes direct interactions with both the G alpha i and the G beta gamma proteins and these interactions are required for downstream signaling to SRC, which is required for signaling through MAPK and PI3K/AKT, as well as for activation of eNOS activity in endothelial cells (Castoria et al, 2001; Wyckoff et al, 2001). Estrogen-stimulation promotes dimerization of the estrogen receptor and dissociation of the heteromeric G-protein (reviewed in Levin, 2015; Schwartz et al, 2016)
R-HSA-9021609 (Reactome) Estrogen treatment stimulates autophosphorylation of SRC at tyrosine 419 (Haynes et al, 2003). SRC catalytic activity is required for signaling to PI3K, AKT and eNOS, as both a kinase dead version of SRC and treatment of cells with a SRC inhibitor abrogate phosphorylation of these downstream targets. SRC interacts with the p85 regulatory subunit of PI3K and in this way promotes assembly of an estrogen-responsive signaling complex in the caveolae (Simoncini et al, 2000; Hayes et al, 2003; Castoria et al, 2001; Castoria et al, 2012; Le Romancer et al, 2008).
R-HSA-9021660 (Reactome) PI3K is recruited to the estrogen receptors at the plasma membrane by virtue of an estrogen-dependent interaction of the p85 regulatory subunit with the estrogen receptor. Estrogen stimulation increases PI3K activity in a manner that also depends on SRC and SRC kinase activity, and results in increased PIP3 production and activation of AKT signaling (Simoncini et al, 2000; Castoria et al, 2001; Castoria et al, 2012; Le Romancer et al, 2008). Activation of AKT signaling downstream of estrogen stimulation drives cellular proliferation through the upregulation of the G1/S cyclin CCND1 (Castoria et al, 2001; Castoria et al, 2004; reviewed in Castoria et al, 2010), and E2 is also required for recruitment of focal adhesion kinase (FAK, also known as PTK2) (Le Romancer et al, 2008). AKT activation additionally stimulates phosphorylation of eNOS at residue 1117, promoting NO release in endothelial cells (Simoncini et al, 2000; Haynes et al, 2000; Hisamoto et al, 2001; Li et al, 2003; Haynes et al, 2003; reviewed in Levin, 2011).
R-HSA-9027670 (Reactome) Palmitoylation of the estrogen receptor is dynamic. Binding of 17 beta-estradiol induces depalmitoylation by an unidentified protein palmitoyl hydrolase, releasing cytosolic ESRs that are free to interact with signaling proteins to initiate rapid non-genomic signaling (Marino et al, 2008; La Rosa et al, 2012; reviewed in Levin, 2005; Arnal et al, 2017). Dynamic palmitoylation cycles also impact the phosphorylation and degradation of ESR1. Mutation of C447 increases the susceptibility of ESR1 to degradation (La Rosa et al, 2012). Mutation of the palmitoyl acceptor cysteine 447 to alanine also abrogates phosphorylation of serine 118, a major N-terminal domain phosphorylation site that contributes to transcriptional activity. As phosphorylation of S118 itself likely occurs as a result of MAPK activation downstream of estrogen-stimulated membrane ESR1, the rapid non-genomic response to estrogen stimulation is interconnected with the classical transcriptional response.
R-HSA-9623341 (Reactome) Estrogen stimulation promotes cell cycle progression in a number of cell lines by upregulating the expression of the G1 cyclin CCND1 (Cyclin D1) (Castoria et al,1999; Castoria et al, 2001; reviewed in Castoria et al, 2010). Estrogen-responsive CCND1 expression is promoted through both the canonical ESR1 receptor and through the alternate receptor GPER1 (Castoria et al, 2001; Castoria et al, 2012; Kanda and Watanabe, 2003; Kanda and Watanabe, 2004). By electrophoretic mobility shift assay, phosphorylated CREB1 binds to a CRE element in the CCND1 promoter, and expression of a CRE-driven CCND1 reporter gene increases upon stimulation of cells with E2 (Kanda and Watanbe, 2003; Kanda and Watanabe, 2004). Expression of CCND1 downstream of E2 and ESR1 or GPER1 stimulates cellular proliferation, consistent with studies in other cell lines (Vivacqua et al, 2006a; Vivacqua et al, 2006b; Albanito et al, 2007; Albanito et al, 2008; Lin et al, 2009; Ariazi et al, 2010; reviewed in Filardo, 2018).
R-HSA-9623355 (Reactome) Expression of CCND1, the gene encoding cyclin D1, is stimulated by treatment of cells with E2. Expression is dependent on ESR1-mediated signaling through the PKA and AKT pathways, and consistent with this, levels of phosphorylated CREB1 increase upon treatment with E2. The CCND1 promoter has a CRE element that is bound by phosphorylated CREB1 upon E2 treatment as assessed by electrophoretic mobility shift assay (Park et al, 2001; Felty et al, 2005).
R-HSA-9623999 (Reactome) BCL2 mRNA and protein levels increase in response to E2 stimulation in a PKA-dependent manner (Grimaldi et al, 2002; Yune et al, 2008). Levels of phosphorylated CREB1 also increase with estrogen stimulation, however direct binding of phosphorylated CREB to the BCL2 promoter has not been demonstrated. Estrogen-dependent BCL2 expression is also dependent on Sp1 (Dong et al, 1999; Yune et al, 2008; reviewed in Ladikou and Kassi, 2017).
R-HSA-9624272 (Reactome) Estrogen-stimulation of ESR1 activates downstream signaling pathways that results in the release of HB-EGF in an IGF- MMP- and EGFR-dependent manner (Razandi et al, 2003; Song et al, 2004; Song et al, 2007; Santen et al, 2009). Based on studies in other systems, candidate MMPs for the cleavage of HB-EGF include MMP2, MMP3, MMP7 and MMP9 (Suzuki et al, 1997; Yu et al, 2002; Razandi et al, 2003). Although direct cleavage of HB-EGF by MMPs downstream of estrogen signaling has not been demonstrated, estrogen-stimulated signaling through EGFR is abrogated after treatment of cells with an HB-EGF neutralizing antibody (Razandi et al, 2003; Song et al, 2007).
R-HSA-9624526 (Reactome) AKT phosphorylation of the pro-apoptotic Forkhead transcription factor FOXO3 and other Foxo family members occurs downstream of E2 stimulation (Richards et al, 2002; reviewed in Levin, 2005). AKT-mediated phosphorylation promotes nuclear export, resulting in a decrease in expression of apoptosis-promoting FOXO3-target genes (Brunet et al, 1999; reviewed in Burgering, 2008).
R-HSA-9624527 (Reactome) AKT-mediated phosphorylation of FOXO3 downstream of estrogen stimulation promotes its inactivation and translocation to the cytosol, interfering with its pro-apoptotic transcription factor activity (Richards et al, 2002; Brunet et al, 1999; reviewed in Levin, 2005; Burgering, 2008).
R-HSA-9625465 (Reactome) The FOS gene encodes FOS, a leucine zipper protein that dimerizes with other FOS, JUN or ATF family members to form the ubiquitous transcription factor complex AP-1 (reviewed in Milde-Langosch, 2005; Hess et al, 2004). AP-1 transcription factors regulate gene expression in response to numerous upstream stimuli, including growth factors, hormones and cytokines and influence proliferation, differentiation and apoptosis, among other processes (reviewed in Shaulina et al, 2002; Thiel and Rossler, 2017).
Transcription of the FOS gene is regulated in part by binding of TCF (a complex of SRF and phosphorylated ELK1) to the serum response element (SRE) in the promoter (Marais et al, 1993; Gille et al, 1995; Duan et al, 2001; reviewed in Treisman, 1995)
R-HSA-9625479 (Reactome) SRF and phosphorylated ELK1 bind to sterol response elements (SRE) in the FOS promoter downstream of E2- and growth factor stimulation (Marais et al, 1993; Gille et al, 1995; Duan et al, 2001; reviewed in Treisman, 1995). FOS gene expression downstream of estrogen stimulation occurs in both an ER alpha (ESR1)- and GPER1-dependent fashion (Maggiolini et al, 2004; Vivacqua et al, 2006; Tsai et al, 2013).
R-HSA-9625482 (Reactome) PTK2 (also known as FAK, focal adhesion kinase) binds to the activated EGFR receptor as assessed by affinity chromatography and co-immunoprecipitation (Sieg et al, 2000; Thelemann et al, 2005; Liu et al, 2010). Stimulation of the EGFR pathway increases PTK2 phosphorylation at Y397, and FAK phosphorylation contributes to cell migration and tumorigenicity (Tamura et al, 1998; Gu et al, 1999; Sieg et al, 2000; Liu et al, 2010; reviewed in Zhu et al, 2018). PTK2-stimulated cell motility depends on integrins and is transduced through phosphorylated MAPK3 and MAPK1 (also known as ERK1 and ERK2) (Sieg et al, 2000; Thelemann et al, 2000; Liu et al, 2005).
R-HSA-9625487 (Reactome) Stimulation of cells with either E2 (beta-estradiol), tamoxifen or G1 (a GPER1 agonist) enhances EGFR-dependent FAK autophosphorylation at Y397 (Sieg et al, 2000; Liu et al, 2010; Tsai et al, 2013). Signaling occurs through both GPER1 and ER alpha (ESR1) and induces cell proliferation and migration through the EGFR-PI3K-ERK pathway (Liu et al, 2010; Tsai et al, 2013; reviewed in Zhu et al, 2018). FAK autophosphorylation is also required for FOS (c-fos) induction downstream of E2 (Liu et al, 2010; Tsai et al, 2013; Maggiolini et al, 2004; Vivacqua et al, 2006a,b).
R-HSA-9625813 (Reactome) S1P binds to its GPCR receptor S1PR3 downstream of E2 stimulation and GPER1 (Sukocheva et al, 2003; Sukocheva et al, 2006). S1P-bound S1PR3 promotes transactivation of the EGFR signaling pathway through the MMP-dependent liberation of HBEGF from the plasma membrane, leading to EGFR and MAPK phosphorylation (Sukocheva et al, 2003; Sukocheva et al, 2006; Kim et al, 2000; Tanimoto et al, 2004; Filardo et al, 2000; Razandi et al, 2003).
R-HSA-9625814 (Reactome) Estrogen stimulation of breast cancer cells promotes ESR1- dependent activation of sphingosine kinase 1 (SPHK1) (Sukocheva et al, 2003; Sukhocheva et al, 2006). SPHK1 catalyzes the formation of sphingosine-1-phosphate (S1P) , a ligand for the GPCR S1PR3 receptor, also known as EDG3 (Hla et al, 2001; Spiegel and Milstein, 2003; Sukocheva et al, 2006). S1P-bound S1PR3 stimulates EGFR transactivation downstream of estradiol stimulation through the MMP-dependent release of HBEGF from the plasma membrane, leading to EGFR and MAPK phosphorylation (Kim et al, 2000; Tanimoto et al, 2004; Filardo et al, 2000; Razandi et al, 2003; Sukocheva et al, 2003; Sukocheva et al, 2006; reviewed in Prossnitz and Barton, 2014).
R-HSA-9632182 (Reactome) ESR1 is methylated by PRMT1 at arginine 260 in response to E2 stimulation. Methylation is required for rapid non-genomic signaling by E2 and promotes the interaction of ESR1 with the p85 regulatory subunit of PI3K, SRC and PTK2 (FAK) (Simoncini et al, 2000; Le Romancer, 2008; reviewed in Arnal, 2017). Although this reaction is shown preceding palmitoylation of ESR1, the sequence of these two events is not established.
R-HSA-9632412 (Reactome) PTK2 (also known as FAK) is co-immunoprecipitated with methylated ESR1 and PI3K after stimulation with estrogen. This interaction depends on ESR1 methylation and on SRC activity, as it is abrogated in the presence of SRC inhibitors or upon PRMT1 depletion (Le Romancer et al, 2008). Phosphorylation of PTK2 appears to be dynamic, as it is lost within 15 minutes of estrogen stimulation, promoting disassembly of the complex. Interaction with PTK2 may contribute to estrogen-stimulated cell motility.
R-HSA-9632858 (Reactome) PKC zeta (PRKCZ) is serine phosphorylated downstream of ESR1 and estradiol stimulation. Serine phosphorylation is required for recruitment of RAS to the ESR1 complex, the estrogen-stimulated translocation of ERK2 to the nucleus and for entry into S phase (Castoria et al, 2004). Mutation of threonine 410, which is required for PRKCZ activation, abolishes serine phosphorylation, suggesting the enzyme autophosphorylates (Castoria et al, 2004).
R-HSA-9632868 (Reactome) CDKN1B (also known as p27 KIP) is an inhibitor of G1 cyclin dependent kinase complexes. CDKN1B interacts with CCND1:CDK4/6 complexes to prevent progression into S phase (reviewed in Vermeulen et al, 2003; Hnit et al, 2015). Relief of CDKN1B-mediated inhibition in response to mitogenic signals is accomplished by multiple mechanisms including localization, transcriptional, translational and proteolytic regulation of CDKN1B.
CDKN1B is phosphorylated at serine 10 during G1 in response to serum and estrogen stimulation, resulting in its XPO1-dependent nuclear export (Ishida et al, 2000; Rodier et al, 2001; Ishida et al, 2003). RAS signaling and PRKCZ-dependent MAPK1 nuclear translocation is required for nuclear export of CDKN1B in response to estrogen stimulation in MCF cells (Aktas et al, 1997; Cheng et al, 1998; Foster et al, 2003; Castoria et al, 2004; Kawada et al, 1997; Migliaccio et al, 1996). Although MAP kinases have been shown to phosphorylate CDKN1B in vitro, it has not been demonstrated in vivo. In another study, UHMK1 was identified as the kinase responsible for S10 phosphorylation in response to serum stimulation (Boehm et al, 2001).
R-HSA-9632873 (Reactome) Estrogen stimulation causes a partial redistribution of CDKN1B into the cytosol in a manner that depends on Ras and PI3K signaling and the atypical PKC zeta (Rodier et al, 2002; Castoria et al, 2004). Nuclear localization of CDKN1B inhibits cell cycle progression (Reynisdottir et al, 1997).
R-HSA-9632906 (Reactome) RAS is recruited to a complex that also contains SRC, PRKCZ and the p85 subunit of PI3K in response to estrogen stimulation (Castoria et al, 2004). RAS signaling downstream of ESR1 contributes to cell cycle progression through the induction of cyclin D transcription and the nuclear export of CDKN1B (Castoria et al, 1999; Castoria et al, 2001; Migliaccio et al, 1996; Rodier et al, 2002; reviewed in Castoria et al, 2010; Arnal et al, 2017).
R-HSA-9632910 (Reactome) MAPK1 (also known as ERK2) translocates to the nucleus in response to estrogen stimulation several cell lines in a manner that also depends on SRC, PI3K and PRCKZ (Castoria et al, 2004). RAS signaling and ERK2 nuclear translocation promotes estrogen-dependent stimulation of cell cycle progression (Castoria et al, 1999; Castoria et al, 2001; Migliaccio et al, 1996; Castoria et al, 2004; Rodier et al, 2002; Foster et al, 2003;reviewed in Castoria et al, 2010).
R-HSA-9632918 (Reactome) Estrogen stimulation promotes nucleotide exchange on RAS in a number of cell lines, leading to RAS signaling and cell cycle progression (Atkas et al, 1997; Cheng et al, 1998; Kawada et al, 1997; Castoria et al, 1999; Castoria et al, 2001). RAS activation depends on recruitment of SRC, PI3K and PRKCZ, and the complex likely also includes SOS, although this has not been explicitly demonstrated (Migliaccio et al, 1996; Castoria et al, 2004; reviewed in Castoria et al, 2010).
R-HSA-9633044 (Reactome) The estrogen receptor binds to the scaffolding protein striatin (STRN) in response to estrogen stimulation in endothelial cells. STRN binding promotes the membrane localization of the receptor and is required for the interaction between ESR1 and G alpha (i), as well as for downstream signaling through AKT, MAPK and eNOS (Lu et al, 2004).
R-HSA-9634584 (Reactome) Estrogen stimulates phosphorylation of the insulin-like growth factor 1 receptor (IGF1R) in a manner that depends on ESR1 but is independent of stimulation by the cognate IGF1 ligand (Richards et al, 1996; Richards et al, 1998; Kleinman et al, 1995; Lee et al, 1999; Kahlert et al, 2000; Song et al, 2002; Song et al, 2004). Estrogen-dependent phosphorylation of IGF1R depends on a physical interaction between the estrogen-bound estrogen receptor and IGF1R and may be promoted by SHC1 and SRC, although the molecular details are not established (Song et al, 2004). In one model, interaction of liganded ESR1 with SHC promotes the activation of SRC and active SRC then phosphorylates IGF1R at tyrosine residues required for SHC interaction. In this way, both SHC and liganded-ESR1 would be brought to IGF1R in a SRC-dependent manner. Consistent with this, SHC has been shown to activate SRC; however, this model has not been rigorously validated (Sato et al, 2002; Song et al, 2004). E2-stimulated IGF1R pathway activation also depends on activation of the MAPK pathway, as IGF1R phosphorylation is abrogated upon treatment of cells with MAPKK inhibitors (Kahlert et al, 2000; Song et al, 2004).
In addition to MAPK pathway activation, E2-dependent IGF1R activation promotes signaling through the EGFR pathway in a manner that depends on MMP2 and MMP9, suggesting that the cross-talk is mediated at the level of liberation of HBEGF from the plasma membrane (Song et al, 2004; Song et al, 2007, Santen et al, 2009). The details of this connection also remain to be fleshed out.
S1P:S1PR3ArrowR-HSA-9624272 (Reactome)
S1P:S1PR3ArrowR-HSA-9625813 (Reactome)
S1PArrowR-HSA-9625814 (Reactome)
S1PR-HSA-9625813 (Reactome)
S1PR3R-HSA-9625813 (Reactome)
SHC1R-HSA-9634584 (Reactome)
SPGR-HSA-9625814 (Reactome)
SPHK1mim-catalysisR-HSA-9625814 (Reactome)
SRFR-HSA-9625479 (Reactome)
STRNR-HSA-9633044 (Reactome)
UHMK1mim-catalysisR-HSA-9632868 (Reactome)
XPO1ArrowR-HSA-9632873 (Reactome)
ZDHHC7, ZDHHC21mim-catalysisR-HSA-9021072 (Reactome)
p-4S,T336-ELK1ArrowR-HSA-198731 (Reactome)
p-4S,T336-ELK1R-HSA-9625479 (Reactome)
p-S10 CDKN1BArrowR-HSA-9632868 (Reactome)
p-S10 CDKN1BArrowR-HSA-9632873 (Reactome)
p-S10 CDKN1BR-HSA-9632873 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4mim-catalysisR-HSA-202127 (Reactome)
p-S133-CREB1 homodimerArrowR-HSA-111916 (Reactome)
p-S133-CREB1 homodimerArrowR-HSA-9623999 (Reactome)
p-S133-CREB1 homodimerR-HSA-9623341 (Reactome)
p-S133-CREB1ArrowR-HSA-199298 (Reactome)
p-S133-CREB1R-HSA-111916 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-198731 (Reactome)
p-T,p-S-AKTmim-catalysisR-HSA-199298 (Reactome)
p-T,p-S-AKTmim-catalysisR-HSA-9624526 (Reactome)
p-T185,Y187 MAPK1 dimerR-HSA-9632910 (Reactome)
p-T32,S253,S315-FOXO3ArrowR-HSA-9624526 (Reactome)
p-T32,S253,S315-FOXO3ArrowR-HSA-9624527 (Reactome)
p-T32,S253,S315-FOXO3R-HSA-9624527 (Reactome)
p-Y1161,1165,1166-IGF1RR-HSA-9634584 (Reactome)
p-Y185,Y187 MAPK1 dimerArrowR-HSA-9632873 (Reactome)
p-Y185,Y187 MAPK1 dimerArrowR-HSA-9632910 (Reactome)
p21 RAS:GDPR-HSA-9632906 (Reactome)
pY-PTK2R-HSA-9632412 (Reactome)
unknown

palmitoyl-(protein)

hydrolase
mim-catalysisR-HSA-9027670 (Reactome)
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