ESR1 (membrane): involvement in growth factors
signaling
Estrogen receptor alpha (ESR1) can occur in the cell in 2 forms: in the nucleus
(ESR1 (nuclear)) and in the plasma membrane
(ESR1 (membrane)) [1], [2]. ESR1 (membrane) is involved
with transduction of the nongenomic effects of estrogen. ESR1
(membrane) can co-opt with Insulin-like growth factor-1 receptor
(IGF-1 receptor) and v-Erb-b2 erythroblastic leukemia viral
oncogene homolog 2 and 3 (ErbB2 and ErbB2)
signaling pathways and uses their downstream common adapter proteins to
transduce signals, leading to the activation of Mitogen-activated protein kinase 1 and 3
(ERK1/2) and/or RAC-alpha serine/threonine kinase
(AKT) cascades [3], [4], [5].
Estradiol is the physiological agonist of
ESR1 (membrane). Estradiol as
classical steroid hormone diffuses through plasma membrane and induces two rapid
processes: 1) binding of ESR1 (membrane) to the adapter
molecule Src homology 2 domain-containing transforming protein 1
(Shc); 2) translocation of ESR1
(membrane) to the cell membrane [6].
Shc binds to docking sites of the IGF-1
receptor. Formation of the ESR1 (membrane)/ Shc/ IGF-1
receptor complex leads to activation of IGF-1
receptor by phosphorylation catalyzed, possibly, by the v-Src sarcoma
viral oncogene homolog (c-Src) [5], [7], [8]. Proline, glutamic acid and leucine rich protein 1
(PELP1) directly binds to both ESR1
(membrane) and c-Src. Coordinate interactions
between PELP1, ESR1 (membrane)
and c-Src lead to c-Src
activation [5], [9].
The adaptor protein Breast cancer anti-estrogen resistance 1
(p130Cas) also participates in ESR1
(membrane)-mediated activation of c-Src
[4], [10].
When ERK1/2 cascade is stimulated by ESR1
(membrane), IGF-1 receptor
activates Shc by
phosphorylation [8], [11], [12].
In addition, c-Src may also
phosphorylate Shc [13].
Shc and Growth factor receptor-bound protein 2
(Grb2) recruit exchange factor Son of sevenless homolog 1
(SOS), and form a protein complex consisting of
Shc / Grb2 /
SOS. Activated SOS stimulates
small GTPase Harvey rat sarcoma virus oncogene 1 (H-RAS) by
converting it from an inactive GDP-bounding state to the active GTP-bounding state. The
activated H-RAS presumably stimulates v-Raf murine sarcoma
viral oncogene homolog B1 (B-Raf)/
MAP kinase kinase 1 and 2 (MEK1
and MEK2)/
ERK1/2 cascade [12], [14], [15].
ERK1/2 can phosphorylate member of ETS oncogene family
Elk-1, and thus stimulate transcription of cellular oncogene
c-Fos [16], [17]. In addition,
ERK1/2 can activate cAMP responsive element binding protein
1 (CREB1) by direct phosphoryling it and/or via activation
of Ribosomal protein S6 kinase, 90kDa, polypeptide 1
(p90RSK1) [18]. It is possible, that
ESR1 (membrane)-dependent stimulation of
Cyclin D1 transcription [10] may be activated by
CREB1 [19] and/or c-Fos
[20].
Another fundamental player for the integration of steroid and growth factor signaling
may be the Phosphoinositide-3-kinase (PI3K)/ RAC-alpha
serine/threonine kinase (AKT). It is shown, that
ESR1 (membrane) may participate in IGF-1
receptor- [21], [22], [23] and
ErbB2/ErbB3-dependent [3] PI3K
activation. Regulatory subunit of the PI3K (PI3K reg class
IA) can be activated by IGF-1 receptor
via Insulin receptor substrate 1
(IRS-1) [22]. PI3K reg class
IA also can be directly activated by ESR1
(membrane) [24] and ErbB3 [3].
PI3K stimulates the conversion of
PI(4,5)P2 to phosphatidylinositol (3,4,5) trisphosphate
(PI(3,4,5)P3). PI(3,4,5)P3
binds to the pleckstrin-homology domain of
AKT, recruits AKT to the plasma
membrane, and exposes AKT to phosphorylation at by
3-phosphoinositide-dependent protein kinase 1 (PDK) [25], [26].
IGF-1 receptor/ ESR1 (membrane)-stimulated
AKT inhibits Glycogen synthase kinase 3 (GSK3
alpha/beta), thus activating proliferation via Cyclin
D1 [22]. ESR1 (membrane)/
ErbB2/ErbB3-dependent AKT induction leads to
activation of transfactors ESR1 (nuclear) [3].
In addition, stimulation of the ESR1 (membrane) results
in rapid activation of the endothelial nitric oxide sythase
(eNOS) and subsequent NO release through the
PI3K/ AKT-dependent pathway
[27].
It is known that p130Cas/
c-Src/ PI3K reg class IA complex
participates in ESR1 (membrane)-induced
ERK activation, but the exact pathway is unknown. It is suggested that
c-Src/ Shc/ H-Ras/ MEK/ ERK and/or PI3K/
PDK/ MEK/ ERK pathway maybe involved in the process. [4], [10].
Signal transduction via the ESR1 (membrane) has
increasingly been found to be important for the cell biological effects of estrogen,
including the antiapoptotic effect, proliferation and regulation of the cell cycle
(S-phase entry) [28], [29], [30].
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