Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

Phospholipase D (PLD) has been suggested to mediate epidermal growth factor (EGF) signaling. However, the molecular mechanism of EGF-induced PLD activation has not yet been elucidated. We investigated the importance of the phosphorylation and compartmentalization of PLD1 in EGF signaling. EGF treatment of COS-7 cells transiently expressing PLD1 stimulated PLD1 activity and induced PLD1 phosphorylation. The EGF-induced phosphorylation of threonine147 was completely blocked and the activity of PLD1 attenuated by point mutations (S2A/T147A/S561A) of PLD1 phosphorylation sites. The expression of a dominant negative PKCα mutant by adenovirus-mediated gene transfer greatly inhibited the phosphorylation and activation of PLD1 induced by EGF in PLD1-transfected COS-7 cells. EGF-induced PLD1 phosphorylation occurred primarily in the caveolin-enriched membrane (CEM) fraction, and the kinetics of PLD1 phosphorylation in the CEM were strongly correlated with PLD1 phosphorylation in the total membrane. Interestingly, EGF-induced PLD1 phosphorylation and activation and the coimmunoprecipitation of PLD1 with caveolin-1 and the EGF receptor in the CEM were significantly attenuated in the palmitoylation-deficient C240S/C241S mutant, which did not localize to the CEM. Immunocytochemical analysis revealed that wild-type PLD1 colocalized with caveolin-1 and the EGF receptor and that phosphorylated PLD1 was localized exclusively in the plasma membrane, although some PLD1 was also detected in vesicular structures. Transfection of wild-type PLD1 but not of C240S/C241S mutant increased EGF-induced raf-1 translocation to the CEM and ERK phosphorylation. This study shows, for the first time, that EGF-induced PLD1 phosphorylation and activation occur in the CEM and that the correct localization of PLD1 to the CEM via palmitoylation is critical for EGF signaling.

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Epidermal Growth Factor Represses Constitutive Androstane Receptor Expression in Primary Human Hepatocytes and Favors Regulation by Pregnane X Receptor

Drug Metabolism and Disposition ◽

10.1124/dmd.117.078683 ◽

2017 ◽

Vol 46 (3) ◽

pp. 223-236 ◽

Cited By ~ 4

Author(s):

Hugues de Boussac ◽

Claire Gondeau ◽

Philippe Briolotti ◽

Cédric Duret ◽

Fridolin Treindl ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Constitutive Androstane Receptor ◽

Pregnane X Receptor ◽

Human Hepatocytes ◽

Receptor Expression ◽

Primary Human Hepatocytes ◽

Epidermal Growth

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Different levels of epidermal growth factor signaling modifies the differentiation of specific cell types in mouse postnatal retina

Archives of Biological Sciences ◽

10.2298/abs190617054i ◽

2019 ◽

Vol 71 (4) ◽

pp. 711-719

Author(s):

Sanja Ivkovic ◽

Irena Jovanovic-Macura ◽

Tijana Antonijevic ◽

Selma Kanazir ◽

Domingos Henrique

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Horizontal Cells ◽

Muller Glia ◽

Müller Glia ◽

Rod Photoreceptors ◽

Infected Cells ◽

Epidermal Growth ◽

Egf Signaling ◽

Different Levels

Epidermal growth factor (EGF) signaling has been implicated in the regulation of the differentiation and proliferation of retinal progenitors. We assessed how different levels of EGF signaling, achieved either by increasing receptor expression or via addition of the exogenous ligand, or an increase in both, can affect the differentiation of progenitors in the first week of postnatal retinal development in the model system of retinal explants (REs). Proliferating progenitor cells in REs were infected with either the control CLV3/ESR-related peptide family (CLE)-green fluorescent protein (GFP)- or with EGF receptor (EGFR)-GFP-expressing retrovirus, and grown in the control medium or in the presence of exogenous EGF (10 ng/mL). The differentiation of infected cells into Muller glia (Sox9+), rod photoreceptors (rhodopsin+) and horizontal cells (calbindin+) was analyzed. In all the examined conditions, infected cells differentiated into Muller glia and rod photoreceptors that normally develop postnatally. Horizontal cells finished their development during the embryonic stages and progenitors infected with control-GFP virus did not differentiate into GFP+/calbindin- in either control or EGFsupplemented medium, however, cells infected with EGFR-GFP differentiated into horizontal cells (GFP+/calbindin+) in both culture conditions. These results imply that altering the levels of EGFR and/or the amount of the EGF ligand can overcome progenitor competence restriction.

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Epidermal growth factor/TNF-α transactivation modulates epithelial cell proliferation and apoptosis in a mouse model of parenteral nutrition

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00142.2011 ◽

2012 ◽

Vol 302 (2) ◽

pp. G236-G249 ◽

Cited By ~ 40

Author(s):

Yongjia Feng ◽

Daniel H. Teitelbaum

Keyword(s):

Growth Factor ◽

Epithelial Cell ◽

Epidermal Growth Factor ◽

Mouse Model ◽

Parenteral Nutrition ◽

Intestinal Epithelial ◽

Tnf Α ◽

Epidermal Growth ◽

Factor Α ◽

Egf Signaling

Epidermal growth factor (EGF) and tumor necrosis factor-α (TNF-α) signaling are critical for effective proliferative and apoptotic actions; however, little is known about the codependency of these signaling pathways in the intestinal epithelium. Because total parenteral nutrition (TPN) is associated with loss of intestinal epithelial cell (IEC) proliferation and increased apoptosis, we utilized a mouse model to explore these transactivation pathways in small bowel epithelium. Mice underwent intravenous cannulation and were given enteral nutrition or TPN for 7 days. Outcomes included IEC proliferation, apoptosis, and survival. To address transactivation or dependence of EGF and TNF on IEC physiology, TNF-α receptor knockout (KO) mice, TNFR1-KO, R2-KO, or R1R2-double KO, were used. Exogenous EGF and pharmacological blockade of ErbB1 were performed in other groups to examine the relevance of the ErB1 pathway. TPN increased IEC TNFR1 and decreased EGF and ErbB1 abundance. Loss of IEC proliferation was prevented by exogenous EGF or blockade of TNFR1. However, EGF action was prevented without effective TNFR2 signaling. Also, blockade of TNFR1 could not prevent loss of IEC proliferation without effective ErbB1 signaling. TPN increased IEC apoptosis and was due to increased TNFR1 signaling. Exogenous EGF or blockade of TNFR1 could prevent increased apoptosis, and both pathways were dependent on effective ErbB1 signaling. Exogenous EGF prevented increased apoptosis in mice lacking TNFR2 signaling. TPN mice had significantly decreased survival vs. controls, and this was associated with the TNFR1 signaling pathway. We concluded that these findings identify critical mechanisms that contribute to TPN-associated mucosal atrophy via altered TNF-α/EGF signaling. It emphasizes the importance of both TNFR1 and TNFR2 pathways, as well as the strong interdependence on an intact EGF/ErbB1 pathway.

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Attenuation of epidermal growth factor (EGF) signaling by growth hormone (GH)

Journal of Endocrinology ◽

10.1530/joe-16-0606 ◽

2017 ◽

Vol 233 (2) ◽

pp. 175-186 ◽

Cited By ~ 2

Author(s):

Lorena González ◽

Johanna G Miquet ◽

Pablo E Irene ◽

M Eugenia Díaz ◽

Soledad P Rossi ◽

...

Keyword(s):

Cell Cycle ◽

Growth Hormone ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Transgenic Mice ◽

Mitogen Activated Protein Kinase ◽

Compensatory Mechanism ◽

Similar Response ◽

Epidermal Growth ◽

Egf Signaling

Transgenic mice overexpressing growth hormone (GH) show increased hepatic protein content of the epidermal growth factor receptor (EGFR), which is broadly associated with cell proliferation and oncogenesis. However, chronically elevated levels of GH result in desensitization of STAT-mediated EGF signal and similar response of ERK1/2 and AKT signaling to EGF compared to normal mice. To ascertain the mechanisms involved in GH attenuation of EGF signaling and the consequences on cell cycle promotion, phosphorylation of signaling mediators was studied at different time points after EGF stimulation, and induction of proteins involved in cell cycle progression was assessed in normal and GH-overexpressing transgenic mice. Results from kinetic studies confirmed the absence of STAT3 and 5 activation and comparable levels of ERK1/2 phosphorylation upon EGF stimulation, which was associated with diminished or similar induction of c-MYC, c-FOS, c-JUN, CYCLIN D1 and CYCLIN E in transgenic compared to normal mice. Accordingly, kinetics of EGF-induced c-SRC and EGFR phosphorylation at activating residues demonstrated that activation of these proteins was lower in the transgenic mice with respect to normal animals. In turn, EGFR phosphorylation at serine 1046/1047, which is implicated in the negative regulation of the receptor, was increased in the liver of GH-overexpressing transgenic mice both in basal conditions and upon EGF stimulus. Increased basal phosphorylation and activation of the p38-mitogen-activated protein kinase might account for increased Ser 1046/1047 EGFR. Hyperphosphorylation of EGFR at serine residues would represent a compensatory mechanism triggered by chronically elevated levels of GH to mitigate the proliferative response induced by EGF.

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Abstract 414: Adipose Angiotensin AT2 Receptors Modulate Thermogenesis Though Interactions with Epidermal Growth Factor Signaling

Hypertension ◽

10.1161/hyp.62.suppl_1.a414 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Henry L Keen ◽

Nicole K Littlejohn ◽

Xuebo Liu ◽

Justin L Grobe ◽

Curt D Sigmund

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Egf Receptor ◽

Gene Set Enrichment Analysis ◽

Rna Seq ◽

Illumina Hiseq ◽

Epidermal Growth ◽

Egf Signaling ◽

The Impact ◽

The Brain

The brain renin-angiotensin system (RAS) stimulates resting metabolic rate (RMR) in part through a mechanism involving suppression of the circulating RAS. This effect appears to be mediated through the loss of tonic adipose angiotensin AT2 receptor (AT2R) activation specifically within inguinal fat. Mice with hyperactivity of the brain RAS (“sRA” mice, expressing human renin via the synapsin promoter and human angiotensinogen via its own promoter) and littermate controls were chronically infused with vehicle or the AT2R agonist, CGP-42112a (CGP, 90 ng/hr, 8 wk, sc). To identify altered signaling pathways in sRA mice and their response to CGP treatment, total RNA was isolated from inguinal adipose tissue and transcript abundance was quantitated by RNA-Seq (50 bp paired reads sequenced with the Illumina HiSeq 2000). There was a significant (P<0.001) change in expression of 123 genes in sRA mice (n=3) compared to littermate controls (n=3), which were generally reversed by CGP treatment (n=4). By manual inspection, we observed that 51 of these genes are associated with epidermal growth factor (EGF) signaling. Consistent with this, Gene Set Enrichment Analysis of the RNA-Seq data demonstrated that genes in the EGF receptor signaling pathway were, as a group, statistically upregulated (P=0.02) in sRA and suppressed (P=0.02) by CGP treatment. Therefore, to further explore the impact of increased EGF signaling on RMR and to isolate a potential modulatory effect of AT2R activation on this response, wildtype C57Bl/6J male mice (9 wk) were infused with EGF (833 ng/hr, 2 wk, sc) with or without co-infusion of CGP. This brief EGF infusion caused a possible increase in RMR (vehicle n=20, 0.173 ± 0.009; EGF n=20, 0.192 ± 0.012 kcal/hr, P=0.13), which was significantly reduced with co-infusion of CGP (90 ng/hr, 2 wk, sc) (EGF+CGP n=17, 0.165 ± 0.005, P<0.05 vs EGF alone; CGP alone n=9, 0.156 ± 0.010). Together these data implicate elevated EGF signaling in the elevated RMR of mice with elevated brain RAS activity. Further, these data suggest a suppressive effect of AT2R activation upon RMR specifically in the context of elevated EGF signaling. Studies utilizing primary inguinal adipose cultures are underway to investigate the molecular basis of the EGF-AT2R interaction.

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EGF signaling promotes the lineage conversion of astrocytes into oligodendroglias

10.21203/rs.3.rs-702088/v1 ◽

2021 ◽

Author(s):

Xinyu Liu ◽

Lesi Xie ◽

Jiao Li ◽

Conghui Li ◽

Kang Zheng ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Cell Fate ◽

Growth Factor Receptor ◽

Transition Process ◽

Precursor Cells ◽

Epidermal Growth ◽

Egf Signaling

Abstract Background The conversion of astrocytes activated by nerve injuries to oligodendrocytes is not only beneficial to axonal remyelination, but also helpful for reversal of glial scar. Recent studies have shown that Sox10 transcription factor can achieve this transdifferentiation process in collaboration with some unknown factors in the pathological microenvironment. The extracellular factors underlying the cell fate switching are not known. Methods Astrocytes were obtained from mouse cortical dissociation culture and purified by differential adherent properties. The lineage conversion of astrocytes into oligodendrocyte lineage cells was carried out by Sox10-expressing virus infection both in vitro and in vivo, meanwhile, epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) inhibitor Gefitinib were adopted to investigate the function of EGF signaling in this fate transition process. Pharmacological inhibition analyses were performed to examine the pathway connecting the EGF with the expression of oligodendrogenic genes and cell fate transdifferentiation. Results EGF treatment facilitated the Sox10-induced transformation of astrocytes to O4+ induced oligodendrocyte precursor cells (iOPCs) in vitro. The transdifferentiation of astrocytes to iOPCs went through two distinct but interconnected processes: (1) dedifferentiation of astrocytes to astrocyte precursor cells (APCs); (2) transformation of APCs to iOPCs, EGF signaling was involved in both processes. And EGF triggered astrocytes to express oligodendrogenic genes Olig1 and Olig2 by activating extracellular signal-regulated kinase 1 and 2 (Erk1/2) pathway. In addition, we discovered that EGF can enhance astrocyte transdifferentiation in injured spinal cord tissues. Conclusions These findings provide strong evidence that EGF facilitates the transdifferentiation of astrocytes to oligodendroglias, and suggest that targeting the EGF-EGFR-Erk1/2 signaling axis may represent a novel therapeutic strategy for myelin repair in injured central nervous system (CNS) tissues.

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Smad7 acts as a negative regulator of the epidermal growth factor (EGF) signaling pathway in breast cancer cells

Cancer Letters ◽

10.1016/j.canlet.2011.09.024 ◽

2012 ◽

Vol 314 (2) ◽

pp. 147-154 ◽

Cited By ~ 16

Author(s):

Sangmin Kim ◽

Jeonghun Han ◽

Se Kyung Lee ◽

Minyoung Koo ◽

Dong Hui Cho ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cancer Cells ◽

Signaling Pathway ◽

Breast Cancer Cells ◽

Negative Regulator ◽

Epidermal Growth ◽

Egf Signaling

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The Polymorphisms of Epidermal Growth Factor-driven Signaling and Cancer Pathogenesis

Sudan Journal of Medical Sciences ◽

10.18502/sjms.v16i2.9289 ◽

2021 ◽

Author(s):

Monica Dugăeșescu ◽

Florentina Mușat ◽

Octavian Andronic

Keyword(s):

Risk Factors ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Signaling Pathway ◽

Malignant Tumors ◽

Cancer Breast ◽

Cancer Pathogenesis ◽

Genes Encoding ◽

Epidermal Growth ◽

Egf Signaling

Background: Epidermal growth factor (EGF) is a stimulating protein for cell proliferation and differentiation. An amplification of its signaling pathway has been frequently reported in numerous malignant tumors. Specific polymorphisms of the genes encoding proteins involved in this cellular pathway may constitute risk factors for carcinogenesis. The aim of this study was to identify the most relevant polymorphisms of EGF and their signaling pathways and their relation to carcinogenesis. Methods: The study included 40 full-text articles published between January 2010 and May 2020, extracted from PubMed, Scopus, Web of Science, and Science Direct databases in May 2020, using the following keywords: EGF OR epidermal growth factor AND polymorphism AND cancer OR neoplasia OR tumor. Results: We identified relevant polymorphisms of the EGF signaling pathway that were involved in the development and progression of hepatocellular carcinoma, esophageal cancer, gastric cancer, colorectal cancer, glioma, lung cancer, breast cancer, cervical cancer, and head and neck cancer. Rs4444903 variants have been widely studied and the association with numerous tumors has been confirmed by multiple studies. Other frequently investigated polymorphisms are –191C/A and –216G>T. Conclusion: The polymorphisms of EGF signaling pathway have been widely studied in connection to various malignancies. Some predisposing variants are common in different forms of cancer. These polymorphisms might be general risk factors for carcinogenesis.

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Epidermal Growth Factor-Dependent Phosphorylation and Ubiquitinylation of MAGE-11 Regulates Its Interaction with the Androgen Receptor

Molecular and Cellular Biology ◽

10.1128/mcb.01672-07 ◽

2008 ◽

Vol 28 (6) ◽

pp. 1947-1963 ◽

Cited By ~ 42

Author(s):

Suxia Bai ◽

Elizabeth M. Wilson

Keyword(s):

Androgen Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Transcriptional Activity ◽

Covalent Modification ◽

Growth Factor Signaling ◽

Epidermal Growth ◽

Coregulatory Proteins ◽

Coregulatory Protein ◽

Egf Signaling

ABSTRACT The androgen receptor (AR) is a ligand-activated transcription factor that interacts with coregulatory proteins during androgen-dependent gene regulation. Melanoma antigen gene protein 11 (MAGE-11) is an AR coregulator that specifically binds the AR NH2-terminal FXXLF motif and modulates the AR NH2- and carboxyl-terminal N/C interaction to increase AR transcriptional activity. Here we demonstrate that epidermal growth factor (EGF) signaling increases androgen-dependent AR transcriptional activity through the posttranslational modification of MAGE-11. EGF in the presence of dihydrotestosterone stabilizes the AR-MAGE complex through the site-specific phosphorylation of MAGE-11 at Thr-360 and ubiquitinylation at Lys-240 and Lys-245. The time-dependent EGF-induced increase in AR transcriptional activity by MAGE-11 is mediated through AR activation functions 1 and 2 in association with the increased turnover of AR and MAGE-11. The results reveal a dynamic mechanism whereby growth factor signaling increases AR transcriptional activity through the covalent modification of an AR-specific coregulatory protein. Sequence conservation of the MAGE-11 phosphorylation and ubiquitinylation sites throughout the MAGE gene family suggests common regulatory mechanisms for this group of cancer-testis antigens.

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