scholarly journals Epidermal growth factor receptor expression and signaling are essential in glutamine's cytoprotective mechanism in heat-stressed intestinal epithelial-6 cells

2013 ◽  
Vol 304 (5) ◽  
pp. G543-G552 ◽  
Author(s):  
Stefanie Niederlechner ◽  
Christine Baird ◽  
Benjamin Petrie ◽  
Erhard Wischmeyer ◽  
Paul E. Wischmeyer
Keyword(s):  
Small Interfering Rna ◽  
Growth Factor Receptor ◽  
Intestinal Epithelial ◽  
Egfr Signaling ◽  
Cellular Protection ◽  
Akt Phosphorylation ◽  
Egfr Expression ◽  
Epidermal Growth ◽  
Interfering Rna

Epidermal growth factor receptor (EGFR) expression and signaling can induce cellular protection after intestinal inflammation. l-Glutamine (GLN) is known to prevent apoptosis after intestinal injury by activating MAPK and phosphatidylinositol 3-kinase (PI3-K)/Akt pathways. However, the role of EGFR expression and signaling in GLN-mediated cellular protection in intestinal epithelial-6 (IEC-6) cells after heat stress (HS) is unknown. To address the role of EGFR in GLN-mediated protection, IEC-6 cells were treated with GLN in the presence or absence of EGFR small interfering RNA, the EGFR tyrosine kinase inhibitor AG1478, the ERK1/2 inhibitor PD98059, the p38MAPK inhibitor SB203580, or the PI3-K/Akt inhibitor LY294002 under basal and HS conditions. GLN-mediated cell survival was measured using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Phosphorylated and/or total levels of EGFR, cleaved caspase-3, poly(ADP-ribose) polymerase-1, ERK1/2, p38MAPK, and Akt were assessed by Western blotting. We showed that HS induced a decrease in total, cytoplasmic, and nuclear EGFR levels in IEC-6 cells, which was prevented by GLN supplementation, leading to attenuated apoptosis via EGFR small interfering RNA. Furthermore, the protective effect of GLN was lessened by AG1478, PD98059, and LY294002 but was not affected by SB203580. AG1478 attenuated GLN-mediated increases in ERK1/2 and decreases in p38MAPK phosphorylation. However, AG1478 had no effect on GLN-mediated augmentations in Akt phosphorylation. In summary, EGFR expression was important in the protective mechanism of GLN, as well as GLN-mediated activation of EGFR tyrosine kinase activity. GLN-mediated EGFR signaling activated ERK1/2 and decreased p38MAPK signaling. However, GLN-mediated Akt phosphorylation after HS seems to be independent of EGFR signaling.

scholarly journals Sex differences in the mechanism of Met5-enkephalin-induced cardioprotection: role of PI3K/Akt

2008 ◽  
Vol 294 (1) ◽  
pp. H302-H310 ◽  
Author(s):  
Zhiping Cao ◽  
Lijuan Liu ◽  
William Packwood ◽  
Matthias Merkel ◽  
Patricia D. Hurn ◽  
...  
Keyword(s):  
Sex Difference ◽  
Small Interfering Rna ◽  
Growth Factor Receptor ◽  
Akt Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Inhibitor ◽  
Epidermal Growth ◽  
Subsequent Activation ◽  
Interfering Rna

Met5-enkephalin (ME)-induced cardioprotection occurs via epidermal growth factor receptor (EGFR) transactivation with the subsequent activation of phosphatidylinositol 3-kinase (PI3K). In the present study, we investigated whether there is a sex difference in ME-elicited PI3K signaling. Neonatal murine cardiomyocytes were isolated by collagenase digestion and subjected to 90 min hypoxia and 180 min reoxygenation at 37°C ( n = 5 to 7 replicates). PI3K/Akt signaling was interrogated using pharmacological inhibitors and small interfering RNA (siRNA). Cell death was assessed by propidium iodide. More than 300 cells were examined for each treatment. The data are presented as means ± SE. There was not a sex difference in the basal content of total Akt. ME (100 μM) elicited comparable protection in both sexes. Wortmannin and the nonselective Akt inhibitor IV completely abolished ME-induced protection in male cardiomyocytes but only attenuated protection in female cardiomyocytes. Isoform-selective knockdown of Akt in males with siRNAs against Akt1/2 completely abolished ME-induced cardioprotection, whereas the siRNAs against Akt3 only attenuated protection of ∼40%. In contrast, in females the siRNAs against Akt1/2 attenuated and against Akt3 eliminated ME-induced cardioprotection. There is not a sex difference in the degree of ME-induced protection, and there is a sex difference in the cardioprotective signaling pathways after the administration of ME; ME-induced cardioprotection in males primarily utilizes a PI3K/Akt1/2 pathway and in females primarily utilizes a PI3K/Akt3 pathway. The incomplete loss of protection in females following the blockade of PI3K suggests that additional factors may facilitate the maintenance or function of activated Akt.

scholarly journals Epidermal Growth Factor Receptor and Abl2 Kinase Regulate Distinct Steps of Human Papillomavirus 16 Endocytosis

2020 ◽  
Vol 94 (11) ◽  
Author(s):  
Carina Bannach ◽  
Pia Brinkert ◽  
Lena Kühling ◽  
Lilo Greune ◽  
M. Alexander Schmidt ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Endocytic Pathway ◽  
Egfr Signaling ◽  
Endocytic Vesicle ◽  
Human Papillomavirus 16 ◽  
Epidermal Growth

ABSTRACT Human papillomavirus 16 (HPV16), the leading cause of cervical cancer, exploits a novel endocytic pathway during host cell entry. This mechanism shares many requirements with macropinocytosis but differs in the mode of vesicle formation. Previous work indicated a role of the epidermal growth factor receptor (EGFR) in HPV16 endocytosis. However, the functional outcome of EGFR signaling and its downstream targets during HPV16 uptake are not well characterized. Here, we analyzed the functional importance of signal transduction via EGFR and its downstream effectors for endocytosis of HPV16. Our findings indicate two phases of EGFR signaling as follows: a—likely dispensable—transient activation with or shortly after cell binding and signaling required throughout the process of asynchronous internalization of HPV16. Interestingly, EGFR inhibition interfered with virus internalization and strongly reduced the number of endocytic pits, suggesting a role for EGFR signaling in the induction of HPV16 endocytosis. Moreover, we identified the Src-related kinase Abl2 as a novel regulator of virus uptake. Inhibition of Abl2 resulted in an accumulation of misshaped endocytic pits, indicating Abl2’s importance for endocytic vesicle maturation. Since Abl2 rather than Src, a regulator of membrane ruffling during macropinocytosis, mediated downstream signaling of EGFR, we propose that the selective effector targeting downstream of EGFR determines whether HPV16 endocytosis or macropinocytosis is induced. IMPORTANCE Human papillomaviruses are small, nonenveloped DNA viruses that infect skin and mucosa. The so-called high-risk HPVs (e.g., HPV16, HPV18, HPV31) have transforming potential and are associated with various anogenital and oropharyngeal tumors. These viruses enter host cells by a novel endocytic pathway with unknown cellular function. To date, it is unclear how endocytic vesicle formation occurs mechanistically. Here, we addressed the role of epidermal growth factor receptor signaling, which has previously been implicated in HPV16 endocytosis and identified the kinase Abl2 as a novel regulator of virus uptake. Since other viruses, such as influenza A virus and lymphocytic choriomeningitis virus, possibly make use of related mechanisms, our findings shed light on fundamental strategies of virus entry and may in turn help to develop new host cell-targeted antiviral strategies.

scholarly journals The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice

Science ◽  
2019 ◽  
Vol 364 (6446) ◽  
pp. 1156-1162 ◽  
Author(s):  
Dannielle D. Engle ◽  
Hervé Tiriac ◽  
Keith D. Rivera ◽  
Arnaud Pommier ◽  
Sean Whalen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor Receptor ◽  
Pancreatic Disease ◽  
Carbohydrate Antigen ◽  
Matricellular Protein ◽  
Egfr Signaling ◽  
Sialyl Lewis ◽  
Egfr Ligands ◽  
Epidermal Growth

Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and β1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewisa, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9–mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.

scholarly journals Impaired Glycolysis Promotes Alcohol Exposure-Induced Apoptosis in HEI-OC1 Cells via Inhibition of EGFR Signaling

2020 ◽  
Vol 21 (2) ◽  
pp. 476 ◽  
Author(s):  
Hyunsook Kang ◽  
Seong Jun Choi ◽  
Kye Hoon Park ◽  
Chi-Kyou Lee ◽  
Jong-Seok Moon
Keyword(s):  
Hearing Loss ◽  
Growth Factor Receptor ◽  
Alcohol Exposure ◽  
Metabolic Dysfunction ◽  
Egfr Signaling ◽  
Akt Phosphorylation ◽  
Egfr Inhibition ◽  
Glycolytic Activity ◽  
Epidermal Growth ◽  
Induced Apoptosis

Glucose metabolism is an important metabolic pathway in the auditory system. Chronic alcohol exposure can cause metabolic dysfunction in auditory cells during hearing loss. While alcohol exposure has been linked to hearing loss, the mechanism by which impaired glycolysis promotes cytotoxicity and cell death in auditory cells remains unclear. Here, we show that the inhibition of epidermal growth factor receptor (EGFR)-induced glycolysis is a critical mechanism for alcohol exposure-induced apoptosis in HEI-OC1 cells. The cytotoxicity via apoptosis was significantly increased by alcohol exposure in HEI-OC1 cells. The glycolytic activity and the levels of hexokinase 1 (HK1) were significantly suppressed by alcohol exposure in HEI-OC1 cells. Mechanistic studies showed that the levels of EGFR and AKT phosphorylation were reduced by alcohol exposure in HEI-OC1 cells. Notably, HK1 expression and glycolytic activity was suppressed by EGFR inhibition in HEI-OC1 cells. These results suggest that impaired glycolysis promotes alcohol exposure-induced apoptosis in HEI-OC1 cells via the inhibition of EGFR signaling.

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