Ligand-independent activation of ESR1 and
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 . 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 , , . Regulators of ESR1 (nuclear) and
ESR2 transcriptional activity activate multiple signaling
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 , . 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
, ,  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) , , .
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) , .
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 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) , , , .
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
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) , , .
During stimulation of cAMP signaling pathway, coactivator
Cyclin D1 enhances 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 activation may be due to more
efficient recruitment of coactivators to the ESR1 (nuclear)
and ESR2 , , . Phosphorylation of ESR1 (nuclear)
increases affinity of coactivators such as NCOA3 . 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 , .
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 .
Ligand-independent transcriptional activation of ERS1
(nuclear) and ESR2 pathways results in
transcription of Trefoil-factor protein 1 (TFF1) , , . TFF1 display a
great number of physiological actions , , . 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 , .
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