scholarly journals Central Role of the EGF Receptor in Neurometabolic Aging

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Sana Siddiqui ◽  
Meng Fang ◽  
Bin Ni ◽  
Daoyuan Lu ◽  
Bronwen Martin ◽  
...  
Keyword(s):  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Egfr Signaling ◽  
Receptor System ◽  
Cardiorespiratory Function ◽  
Epidermal Growth ◽  
Signaling Domains ◽  
Cellular Stressors ◽  
The Brain

A strong connection between neuronal and metabolic health has been revealed in recent years. It appears that both normal and pathophysiological aging, as well as neurodegenerative disorders, are all profoundly influenced by this “neurometabolic” interface, that is, communication between the brain and metabolic organs. An important aspect of this “neurometabolic” axis that needs to be investigated involves an elucidation of molecular factors that knit these two functional signaling domains, neuronal and metabolic, together. This paper attempts to identify and discuss a potential keystone signaling factor in this “neurometabolic” axis, that is, the epidermal growth factor receptor (EGFR). The EGFR has been previously demonstrated to act as a signaling nexus for many ligand signaling modalities and cellular stressors, for example, radiation and oxidative radicals, linked to aging and degeneration. The EGFR is expressed in a wide variety of cells/tissues that pertain to the coordinated regulation of neurometabolic activity. EGFR signaling has been highlighted directly or indirectly in a spectrum of neurometabolic conditions, for example, metabolic syndrome, diabetes, Alzheimer’s disease, cancer, and cardiorespiratory function. Understanding the positioning of the EGFR within the neurometabolic domain will enhance our appreciation of the ability of this receptor system to underpin highly complex physiological paradigms such as aging and neurodegeneration.

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 A Tale of Two Cbls: Interplay of c-Cbl and Cbl-b in Epidermal Growth Factor Receptor Downregulation

2008 ◽  
Vol 28 (9) ◽  
pp. 3020-3037 ◽  
Author(s):  
Steven Pennock ◽  
Zhixiang Wang
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Wild Type ◽  
Receptor Downregulation ◽  
Epidermal Growth ◽  
Precise Role ◽  
Second Peak

ABSTRACT The precise role of Cbl in epidermal growth factor (EGF) receptor (EGFR) endocytosis and trafficking remains to be fully uncovered. Here, we showed that mutant EGFR1044, which was truncated after residue 1044, did not associate with c-Cbl and was not ubiquitinated initially in response to EGF but was internalized with kinetics similar to those of wild-type EGFR. This finding indicates that c-Cbl-mediated ubiquitination is not required for EGF-induced EGFR endocytosis. We also showed that the previously identified internalization-deficient mutant receptor EGFR1010LL/AA bound to c-Cbl and was fully ubiquitinated in response to EGF, which indicates that c-Cbl binding and ubiquitination are not sufficient for EGFR internalization. We next investigated EGFR trafficking following EGFR internalization. We found that c-Cbl disassociation from EGFR occurred well in advance of EGFR degradation and that this event was concurrent with the selective dephosphorylation of EGFR at Y1045. This finding suggests that once EGFR is ubiquitinated, continual Cbl association is not required for EGFR degradation. Because EGFR1044 is ubiquitinated and degraded similarly to wild-type EGFR, we examined the role of another prominent Cbl homologue, Cbl-b, and found that Cbl-b was associated with both EGFR and EGFR1044. Further study showed that Cbl-b bound to EGFR at two regions: one in the C-terminal direction from residue 1044 and one in the N-terminal direction from residue 958. Moreover, Cbl-b association with EGFR rose markedly following a decrease in c-Cbl association, corresponding to a second peak of EGFR ubiquitination occurring later in EGFR trafficking. Using RNA interference to knock down both c-Cbl and Cbl-b, we were able to abolish EGFR downregulation. This knockdown had no affect on the rate of EGF-induced EGFR internalization. We found that the two Cbls accounted for total receptor ubiquitination and that while c-Cbl and Cbl-b are each alone sufficient to effect EGFR degradation, both are involved in the physiological, EGF-mediated process of receptor downregulation. Furthermore, these data ultimately reveal a previously unacknowledged temporal interplay of two major Cbl homologues with the trafficking of EGFR.

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 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.

Astrocyte mitogen inhibitor related to epidermal growth factor receptor

Science ◽  
1988 ◽  
Vol 240 (4860) ◽  
pp. 1784-1786 ◽  
Author(s):  
M Nieto-Sampedro
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Biological Activities ◽  
Growth Factor Receptor ◽  
Intracerebral Injection ◽  
Injured Brain ◽  
Epidermal Growth ◽  
The Brain ◽  
Stimulation Of

Epidermal growth factor (EGF) is a well-characterized polypeptide hormone with diverse biological activities, including stimulation of astrocyte division. A soluble astrocyte mitogen inhibitor, immunologically related to the EGF receptor, is present in rat brain. Injury to the brain causes a time-dependent reduction in the levels of this inhibitor and the concomitant appearance of EGF receptor on the astrocyte surface. Intracerebral injection of antibody capable of binding the inhibitor caused the appearance of numerous reactive astrocytes. EGF receptor-related inhibitors may play a key role in the control of glial cell division in both normal and injured brain.

scholarly journals The Role of Epidermal Growth Factor Receptor in Cancer Metastasis and Microenvironment

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Takamitsu Sasaki ◽  
Kuniyasu Hiroki ◽  
Yuichi Yamashita
Keyword(s):  
Cancer Cells ◽  
Cancer Metastasis ◽  
Surgical Techniques ◽  
Growth Factor Receptor ◽  
Host Cells ◽  
Colon Cancer Cells ◽  
Egfr Signaling ◽  
Epidermal Growth ◽  
Multiple Interactions

Despite significant improvements in diagnosis, surgical techniques, and advancements in general patient care, the majority of deaths from cancer are caused by the metastases. There is an urgent need for an improved understanding of the cellular and molecular factors that promote cancer metastasis. The process of cancer metastasis depends on multiple interactions between cancer cells and host cells. Studies investigating the TGFα-EGFR signaling pathways that promote the growth and spread of cancer cells. Moreover, the signaling activates not only tumor cells, but also tumor-associated endothelial cells. TGFα-EGFR signaling in colon cancer cells creates a microenvironment that is conducive for metastasis, providing a rationale for efforts to inhibit EGFR signaling in TGFα-positive cancers. In this review, we describe the recent advances in our understanding of the molecular basis of cancer metastasis.

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