Development Ligand-independent activation of ESR1 and ESR2
Ligand-independent activation of ESR1 and ESR2 In addition to the conventional hormone-dependent regulation of activity of Estrogenreceptor alpha and beta ( ESR1(nuclear) and ESR2 respectively), there is across-talk between signal transduction pathways and estrogen receptors .Epidermal growth factor ( EGF ), Insulin-like growth factor-1 ( IGF-1 ),stimulators of cAMP-dependent signaling pathway regulate transcriptional activity of theESR1(nuclear) and ESR2 in the absence of ligand , , . Regulators of ESR1 (nuclear) and ESR2transcriptional activity activate multiple signaling pathways. EGF and IGF-1 activate ESR1(nuclear) by binding to thecorresponding receptors (Epidermal growth factor receptor ( EGFR ) andInsulin-like growth factor 1 receptor ( IGF-1 receptor ) respectively) followed bystimulation of mitogen-activated protein kinases (MAPK) cascade - signaling pathway.ESR2 is activated only by EGF signaling , .The adaptors Src homology 2 domain-containing transforming protein 1 ( Shc ) andGrowth factor receptor-bound protein 2 ( Grb2 ) recruit exchange factor Son ofsevenless homolog ( SOS ), forming a protein complex Shc/ Grb2/SOS. Activated SOS stimulates small GTPase v-Ha-ras Harvey rat sarcomaviral oncogene homolog ( H-Ras ) by its conversion from the inactive GDP-boundingstate to the active GTP-bounding state. The activated H-RAS stimulates v-raf-1murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated proteinkinase kinases 1 and 2 ( MEK1(MAP2K1) MEK2(MAP2K2) )/ Mitogen activated proteinkinases 1-3 ( ERK1/2 ) cascade, which leads to higher transcriptional activity ofESR1 (nuclear) and ESR2. ERK1/2 can activate ESR1 (nuclear)and ESR2 by direct phosphorylation , ,  or via phosphorylation of coregulatory proteins such as Nuclear receptorco-activators 1, 2 and 3 ( NCOA1 (SRC1), NCOA2 (GRIP1/TIF2) and NCOA3(pCIP/SRC3), respectively) , , . EGF also activates Ribosomal protein S6 kinase, 90kDa, polypeptide 1 (p90RSK1 ) (most probably through MAP kinases pathway), which phosphorylates andenhances transcriptional activity of ESR1 (nuclear) ,  . The second pathway which stimulates exclusively ESR1 (nuclear) by EGFand IGF-1 includes activation Phosphoinositide-3-kinase ( PI3K )/ V-aktmurine thymoma viral oncogene homolog 1 ( AKT(PKB) ) cascade. EGFR(directly) and IGF-1 receptor (via Insulin receptor substrate 1 ( IRS-1 ))activate PI3K which converts phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2 ) to phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3 ). PtdIns(3,4,5)P3 associates with the inner face of theplasma membrane promoting the recruitment and activation of the AKT(PKB). BothPI3K and AKT(PKB) phosphorylate ESR1 (nuclear) ,, , . Neuregulin-1 also activates ESR1 (nuclear) in aligand-independent manner via PI3K/ AKT(PKB) pathway. Neuregulin-1interacts with an v-erb-b2 erythroblastic leukemia viral oncogene homolog 2,neuro/glioblastoma derived oncogene homolog of ( ErbB2 )/ v-erb-b2 erythroblasticleukemia viral oncogene homolog 3 ( ErbB3 ) heterodimers; activated ErbB3recruits and activates PI3K and, consequently, AKT(PKB) and ESR1(nuclear) phosphorylated by AKT(PKB) . Stimulation of cAMP/ Protein kinase, cAMP-dependent ( PKA ) signalinglikely proceeds via G-protein alpha-s which activates Adenylate cyclase.Activation of PKA by cAMP is the third ligand-independent signaling pathwaywhich stimulates ESR1 (nuclear) , , . During stimulation of cAMP signaling pathway, coactivator Cyclin D1enhances transcriptional activity of ESR1 (nuclear) in a ligand-independent manner, . Co-regulatory proteins NCOA1 (SRC1), NCOA2 (GRIP1/TIF2) and NCOA3(pCIP/SRC3) in response to growth factors overall ligand-independent ESR activationmay be due to more efficient recruitment of coactivators to the ESR1 (nuclear) andESR2 , , . Phosphorylation ofESR1 (nuclear) increases affinity of coactivators such as NCOA3 . ESR1 (nuclear) -coactivator complex then recruits integratorproteins such as CREB binding protein ( CBP ) and E1A binding protein p300 (p300 ), which by DNA looping brings the receptor-containing regulatory region ofthe gene into proximity with the actual transcriptional start site ,. Caveolin 1, caveolae protein, 22kDa ( Caveolin-1 ) is yet another co-activatorof ESR1 (nuclear) in a ligand-independent manner, which drives ERK-independent phosphorylation and activation of AF-1 domain . Ligand-independent transcriptional activation of ERS1 (nuclear) and ESR2pathways results in transcription of Trefoil-factor protein 1 ( TFF1 ) , , . TFF1 display a great number ofphysiological actions , , . Its role inligand-independent ESR activation is not yet resolved. ERS1 (nuclear) andESR2 inhibit cell migration and invasion and ESR2 inhibits cellproliferation in a ligand-independent manner , .