Development - Membrane-bound ESR1: interaction with growth factors signaling

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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