Pathway Map Details

Development_Ligand-independent activation of ESR1 and ESR2

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MEK2(MAP2K2), NCOA3, c-Raf-1, AKT(PKB), ERK2 (MAPK1), EGFR, PI3K cat class IA, CBP, ErbB3, PIP3, ErbB2, Shc, ERK1 (MAPK3), ESR1 (nuclear), ATP, PDK (PDPK1), NCOA2 , PKA-cat ,, NCOA1 , Caveolin-1, Galpha(s)-specific GPCRs, H-Ras, IGF-1 receptor,, IGF-1, EGF, p300, PKA-reg , PI3K reg class IA, GRB2, p90RSK1, SOS, PIP2, ESR2, MEK1(MAP2K1), IRS-1, Cyclin D1, Neuregulin 1, G-protein alpha-s, ERK1/2, Adenylate cyclase, cAMP, TFF1


Ligand-independent activation of ESR1 and ESR2

In addition to the conventional hormone-dependent regulation of activity of Estrogen receptor alpha and beta ( ESR1(nuclear) and ESR2 respectively), there is a cross-talk between signal transduction pathways and estrogen receptors [1]. Epidermal growth factor ( EGF ), Insulin-like growth factor-1 ( IGF-1 ), stimulators of cAMP-dependent signaling pathway regulate transcriptional activity of the ESR1(nuclear) and ESR2 in the absence of ligand [2], [3], [4]. Regulators of ESR1 (nuclear) and ESR2 transcriptional activity activate multiple signaling pathways.

EGF and IGF-1 activate ESR1(nuclear) by binding to the corresponding receptors (Epidermal growth factor receptor ( EGFR ) and Insulin-like growth factor 1 receptor ( IGF-1 receptor ) respectively) followed by stimulation of mitogen-activated protein kinases (MAPK) cascade - signaling pathway. ESR2 is activated only by EGF signaling [5], [6]. The adaptors Src homology 2 domain-containing transforming protein 1 ( Shc ) and Growth factor receptor-bound protein 2 ( Grb2 ) recruit exchange factor Son of sevenless homolog ( SOS ), forming a protein complex Shc/ Grb2/ SOS. Activated SOS stimulates small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) by its conversion from the inactive GDP-bounding state to the active GTP-bounding state. The activated H-RAS stimulates v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1) MEK2(MAP2K2) )/ Mitogen activated protein kinases 1-3 ( ERK1/2 ) cascade, which leads to higher transcriptional activity of ESR1 (nuclear) and ESR2. ERK1/2 can activate ESR1 (nuclear) and ESR2 by direct phosphorylation [5], [7], [8] or via phosphorylation of coregulatory proteins such as Nuclear receptor co-activators 1, 2 and 3 ( NCOA1 (SRC1), NCOA2 (GRIP1/TIF2) and NCOA3 (pCIP/SRC3), respectively) [9], [10], [11].

EGF also activates Ribosomal protein S6 kinase, 90kDa, polypeptide 1 ( p90RSK1 ) (most probably through MAP kinases pathway), which phosphorylates and enhances transcriptional activity of ESR1 (nuclear) [12], [8] .

The second pathway which stimulates exclusively ESR1 (nuclear) by EGF and IGF-1 includes activation Phosphoinositide-3-kinase ( PI3K )/ V-akt murine 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 the plasma membrane promoting the recruitment and activation of the AKT(PKB). Both PI3K and AKT(PKB) phosphorylate ESR1 (nuclear) [13], [14], [8], [15].

Neuregulin-1 also activates ESR1 (nuclear) in a ligand-independent manner via PI3K/ AKT(PKB) pathway. Neuregulin-1 interacts with an v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog of ( ErbB2 )/ v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 ( ErbB3 ) heterodimers; activated ErbB3 recruits and activates PI3K and, consequently, AKT(PKB) and ESR1 (nuclear) phosphorylated by AKT(PKB) [16].

Stimulation of cAMP/ Protein kinase, cAMP-dependent ( PKA ) signaling likely proceeds via G-protein alpha-s which activates Adenylate cyclase. Activation of PKA by cAMP is the third ligand-independent signaling pathway which stimulates ESR1 (nuclear) [2], [8], [15].

During stimulation of cAMP signaling pathway, coactivator Cyclin D1 enhances transcriptional activity of ESR1 (nuclear) in a ligand-independent manner [17], [1].

Co-regulatory proteins NCOA1 (SRC1), NCOA2 (GRIP1/TIF2) and NCOA3 (pCIP/SRC3) in response to growth factors overall ligand-independent ESR activation may be due to more efficient recruitment of coactivators to the ESR1 (nuclear) and ESR2 [10], [18], [19]. Phosphorylation of ESR1 (nuclear) increases affinity of coactivators such as NCOA3 [15]. ESR1 (nuclear) -coactivator complex then recruits integrator proteins such as CREB binding protein ( CBP ) and E1A binding protein p300 ( p300 ), which by DNA looping brings the receptor-containing regulatory region of the gene into proximity with the actual transcriptional start site [10], [18].

Caveolin 1, caveolae protein, 22kDa ( Caveolin-1 ) is yet another co-activator of ESR1 (nuclear) in a ligand-independent manner, which drives ERK -independent phosphorylation and activation of AF-1 domain [20].

Ligand-independent transcriptional activation of ERS1 (nuclear) and ESR2 pathways results in transcription of Trefoil-factor protein 1 ( TFF1 ) [21], [14], [18]. TFF1 display a great number of physiological actions [22], [23], [24]. Its role in ligand-independent ESR activation is not yet resolved. ERS1 (nuclear) and ESR2 inhibit cell migration and invasion and ESR2 inhibits cell proliferation in a ligand-independent manner [25], [26].


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