Extra-nuclear estrogen signaling (Homo sapiens)
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Description
In addition to its well-characterized role in estrogen-dependent transcription, estrogen (beta-estradiol, also known as E2) also plays a rapid, non-genomic role through interaction with receptors localized at the plasma membrane by virtue of dynamic palmitoylation. Estrogen receptor palmitoylation is a prerequisite for the E2-dependent activation of extra-nuclear signaling both in vitro and in animal models (Acconcia et al, 2004; Acconcia et al, 2005; Marino et al, 2006; Marino and Ascenzi, 2006). Non-genomic signaling through the estrogen receptor ESR1 also depends on receptor arginine methylation by PMRT1 (Pedram et al, 2007; Pedram et al, 2012; Le Romancer et al, 2008; reviewed in Arnal, 2017; Le Romancer et al, 2011 ).
E2-evoked extra-nuclear signaling is independent of the transcriptional activity of estrogen receptors and occurs within seconds to minutes following E2 administration to target cells. Extra-nuclear signaling consists of the activation of a plethora of signaling pathways including the RAF/MAP kinase cascade and the PI3K/AKT signaling cascade and governs processes such as apoptosis, cellular proliferation and metastasis (reviewed in Hammes et al, 2007; Handa et al, 2012; Lange et al, 2007; Losel et al, 2003; Arnal et al, 2017; Le Romancer et al, 2011). ESR-mediated signaling also cross-talks with receptor tyrosine kinase, NF- kappa beta and GPCR signaling pathways by modulating the post-translational modification of enzymes and other proteins and regulating second messengers (reviewed in Arnal et al, 2017; Schwartz et al, 2016; Boonyaratanakornkit, 2011; Biswas et al, 2005). In the nervous system, E2 affects neural functions such as cognition, behaviour, stress responses and reproduction in part by inducing such rapid extra-nuclear responses (Farach-Carson and Davis, 2003; Losel et al, 2003), while in endothelial cells, non-genomic ESR-dependent signaling also regulates vasodilation through the eNOS pathway (reviewed in Levin, 2011).
Extra-nuclear signaling additionally cross-talks with nuclear estrogen receptor signaling and is required to control ER protein stability (La Rosa et al, 2012)
Recent data have demonstrated that the membrane ESR1 can interact with various endocytic proteins to traffic and signal within the cytoplasm. This receptor intracellular trafficking appears to be dependent on the phyical interaction of ESR1 with specific trans-membrane receptors such as IGR-1R and beta 1-integrin (Sampayo et al, 2018) View original pathway at Reactome.
E2-evoked extra-nuclear signaling is independent of the transcriptional activity of estrogen receptors and occurs within seconds to minutes following E2 administration to target cells. Extra-nuclear signaling consists of the activation of a plethora of signaling pathways including the RAF/MAP kinase cascade and the PI3K/AKT signaling cascade and governs processes such as apoptosis, cellular proliferation and metastasis (reviewed in Hammes et al, 2007; Handa et al, 2012; Lange et al, 2007; Losel et al, 2003; Arnal et al, 2017; Le Romancer et al, 2011). ESR-mediated signaling also cross-talks with receptor tyrosine kinase, NF- kappa beta and GPCR signaling pathways by modulating the post-translational modification of enzymes and other proteins and regulating second messengers (reviewed in Arnal et al, 2017; Schwartz et al, 2016; Boonyaratanakornkit, 2011; Biswas et al, 2005). In the nervous system, E2 affects neural functions such as cognition, behaviour, stress responses and reproduction in part by inducing such rapid extra-nuclear responses (Farach-Carson and Davis, 2003; Losel et al, 2003), while in endothelial cells, non-genomic ESR-dependent signaling also regulates vasodilation through the eNOS pathway (reviewed in Levin, 2011).
Extra-nuclear signaling additionally cross-talks with nuclear estrogen receptor signaling and is required to control ER protein stability (La Rosa et al, 2012)
Recent data have demonstrated that the membrane ESR1 can interact with various endocytic proteins to traffic and signal within the cytoplasm. This receptor intracellular trafficking appears to be dependent on the phyical interaction of ESR1 with specific trans-membrane receptors such as IGR-1R and beta 1-integrin (Sampayo et al, 2018) View original pathway at Reactome.
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DataNodes
ligands:p-6Y
EGFR:PTK2ligands:p-6Y EGFR
dimer:p-Y397 PTK2ligands:p-6Y EGFR
dimergene:SRF:p-4S,T336
ELK1G-protein Gi
(inactive)oxide: NOS3 activation and
regulationThe NOS enzymes share a common basic structural organization and requirement for substrate cofactors for enzymatic activity. A central calmodulin-binding motif separates an NH2-terminal oxygenase domain from a COOH-terminal reductase domain. Binding sites for cofactors NADPH, FAD, and FMN are located within the reductase domain, while binding sites for tetrahydrobiopterin (BH4) and heme are located within the oxygenase domain. Once calmodulin binds, it facilitates electron transfer from the cofactors in the reductase domain to heme enabling nitric oxide production. Both nNOS and eNOS contain an additional insert (40-50 amino acids) in the middle of the FMN-binding subdomain that serves as autoinhibitory loop, destabilizing calmodulin binding at low calcium levels and inhibiting electron transfer from FMN to the heme in the absence of calmodulin. iNOS does not contain this insert.
In this Reactome pathway module, details of eNOS activation and regulation are annotated. Originally identified as endothelium-derived relaxing factor, eNOS derived NO is a critical signaling molecule in vascular homeostasis. It regulates blood pressure and vascular tone, and is involved in vascular smooth muscle cell proliferation, platelet aggregation, and leukocyte adhesion. Loss of endothelium derived NO is a key feature of endothelial dysfunction, implicated in the pathogenesis of hypertension and atherosclerosis. The endothelial isoform eNOS is unique among the nitric oxide synthase (NOS) family in that it is co-translationally modified at its amino terminus by myristoylation and is further acylated by palmitoylation (two residues next to the myristoylation site). These modifications target eNOS to the plasma membrane caveolae and lipid rafts.
Factors that stimulate eNOS activation and nitric oxide (NO) production include fluid shear stress generated by blood flow, vascular endothelial growth factor (VEGF), bradykinin, estrogen, insulin, and angiopoietin. The activity of eNOS is further regulated by numerous post-translational modifications, including protein-protein interactions, phosphorylation, and subcellular localization.
Following activation, eNOS shuttles between caveolae and other subcellular compartments such as the noncaveolar plasma membrane portions, Golgi apparatus, and perinuclear structures. This subcellular distribution is variable depending upon cell type and mode of activation.
Subcellular localization of eNOS has a profound effect on its ability to produce NO as the availability of its substrates and cofactors will vary with location. eNOS is primarily particulate, and depending on the cell type, eNOS can be found in several membrane compartments: plasma membrane caveolae, lipid rafts, and intracellular membranes such as the Golgi complex.
During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).
During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.
p-T410 PRKCZ:p21
RAS:GDPp-T410 PRKCZ:p21
RAS:GTPThe importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
palmitoyl-(protein)
hydrolaseAnnotated Interactions
ligands:p-6Y
EGFR:PTK2ligands:p-6Y
EGFR:PTK2ligands:p-6Y
EGFR:PTK2ligands:p-6Y EGFR
dimer:p-Y397 PTK2ligands:p-6Y EGFR
dimer:p-Y397 PTK2ligands:p-6Y EGFR
dimergene:SRF:p-4S,T336
ELK1gene:SRF:p-4S,T336
ELK1G-protein Gi
(inactive)p-T410 PRKCZ:p21
RAS:GDPp-T410 PRKCZ:p21
RAS:GDPp-T410 PRKCZ:p21
RAS:GTPp-T410 PRKCZ:p21
RAS:GTPOnce recruited, SRC is activated by autophosphorylation at tyrosine 419, which in turn is required for the recruitment and activation of PI3K and AKT, and ultimately for the activation of endothelial nitric oxide synthase (eNOS) and promotion of AKT-dependent cellular proliferation (Haynes et al, 2000; Simoncini et al, 2000; Haynes et al, 2003; Li et al, 2007; reviewed in Kim and Bender, 2005; Hammes and Levin, 2011; Le Romancer et al, 2011: Castoria et al, 2010). Formation of an eNOS signaling complex also depends on interaction between the estrogen receptor and heterotrimeric G-proteins (Wyckoff et al, 2001; reviewed in Schwartz, 2016).
Transcription of the FOS gene is regulated in part by binding of TCF (a complex of SRF and phosphorylated ELK1) to the serum response element (SRE) in the promoter (Marais et al, 1993; Gille et al, 1995; Duan et al, 2001; reviewed in Treisman, 1995)
CDKN1B is phosphorylated at serine 10 during G1 in response to serum and estrogen stimulation, resulting in its XPO1-dependent nuclear export (Ishida et al, 2000; Rodier et al, 2001; Ishida et al, 2003). RAS signaling and PRKCZ-dependent MAPK1 nuclear translocation is required for nuclear export of CDKN1B in response to estrogen stimulation in MCF cells (Aktas et al, 1997; Cheng et al, 1998; Foster et al, 2003; Castoria et al, 2004; Kawada et al, 1997; Migliaccio et al, 1996). Although MAP kinases have been shown to phosphorylate CDKN1B in vitro, it has not been demonstrated in vivo. In another study, UHMK1 was identified as the kinase responsible for S10 phosphorylation in response to serum stimulation (Boehm et al, 2001).
In addition to MAPK pathway activation, E2-dependent IGF1R activation promotes signaling through the EGFR pathway in a manner that depends on MMP2 and MMP9, suggesting that the cross-talk is mediated at the level of liberation of HBEGF from the plasma membrane (Song et al, 2004; Song et al, 2007, Santen et al, 2009). The details of this connection also remain to be fleshed out.
palmitoyl-(protein)
hydrolase