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Results: 1 to 10 of 137

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Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer.
Young CD, Zimmerman LJ, Hoshino D, Formisano L, Hanker AB, Gatza ML, Morrison MM, Moore PD, Whitwell CA, Dave B, Stricker T, Bhola NE, Silva GO, Patel P, Brantley-Sieders DM, Levin M, Horiates M, Palma NA, Wang K, Stephens PJ, Perou CM, Weaver AM, O'Shaughnessy JA, Chang JC, Park BH, Liebler DC, Cook RS, Arteaga CL
(2015) Mol Cell Proteomics 14: 1959-76
MeSH Terms: Amphiregulin, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Chromatography, Liquid, Class I Phosphatidylinositol 3-Kinases, Disease-Free Survival, Down-Regulation, Epidermal Growth Factor, ErbB Receptors, Extracellular Matrix, Extracellular Signal-Regulated MAP Kinases, Female, Humans, Mice, Nude, Mutation, Neoplasm Proteins, Paracrine Communication, Phosphatidylinositol 3-Kinases, Protein Binding, Protein Kinase Inhibitors, Proteomics, Signal Transduction, Tandem Mass Spectrometry, Up-Regulation
Show Abstract · Added February 15, 2016
Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
3 Members
0 Resources
26 MeSH Terms
Loss of hepatocyte EGFR has no effect alone but exacerbates carbon tetrachloride-induced liver injury and impairs regeneration in hepatocyte Met-deficient mice.
Scheving LA, Zhang X, Stevenson MC, Threadgill DW, Russell WE
(2015) Am J Physiol Gastrointest Liver Physiol 308: G364-77
MeSH Terms: Animals, Carbon Tetrachloride, Chemical and Drug Induced Liver Injury, Cyclin A, Cyclin D1, Epidermal Growth Factor, ErbB Receptors, Hepatocytes, Liver Regeneration, Mice, Neuregulin-1, Proto-Oncogene Proteins c-met, Receptor, ErbB-3
Show Abstract · Added May 5, 2016
The role(s) of the epidermal growth factor receptor (EGFR) in hepatocytes is unknown. We generated a murine hepatocyte specific-EGFR knockout (KO) model to evaluate how loss of hepatocellular EGFR expression affects processes such as EGF clearance, circulating EGF concentrations, and liver regeneration following 70% resection or CCl4-induced centrilobular injury. We were able to disrupt EGFR expression effectively in hepatocytes and showed that the ability of EGF and heregulin (HRG) to phosphorylate EGFR and ERBB3, respectively, required EGFR. Loss of hepatocellular EGFR impaired clearance of exogenous EGF from the portal circulation but paradoxically resulted in reduced circulating levels of endogenous EGF. This was associated with decreased submandibular salivary gland production of EGF. EGFR disruption did not result in increased expression of other ERBB proteins or Met, except in neonatal mice. Liver regeneration following 70% hepatectomy revealed a mild phenotype, with no change in cyclin D1 expression and slight differences in cyclin A expression compared with controls. Peak 5-bromo-2'-deoxyuridine labeling was shifted from 36 to 48 h. Centrilobular damage and regenerative response induced by carbon tetrachloride (CCl4) were identical in the KO and wild-type mice. In contrast, loss of Met increased CCl4-induced necrosis and delayed regeneration. Although loss of hepatocellular EGFR alone did not have an effect in this model, EGFR-Met double KOs displayed enhanced necrosis and delayed liver regeneration compared with Met KOs alone. This suggests that EGFR and Met may partially compensate for the loss of the other, although other compensatory mechanisms can be envisioned.
Copyright © 2015 the American Physiological Society.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Site-specific mapping and quantification of protein S-sulphenylation in cells.
Yang J, Gupta V, Carroll KS, Liebler DC
(2014) Nat Commun 5: 4776
MeSH Terms: Acetylation, Cell Line, Tumor, Cysteine, Epidermal Growth Factor, Epithelial Cells, Gene Expression, Humans, Hydrogen Peroxide, Hypoxia-Inducible Factor 1, alpha Subunit, Molecular Sequence Annotation, Oxidation-Reduction, Peptide Mapping, Phosphorylation, Protein Processing, Post-Translational, Sirtuins, Sulfenic Acids, Ubiquitination
Show Abstract · Added January 20, 2015
Cysteine S-sulphenylation provides redox regulation of protein functions, but the global cellular impact of this transient post-translational modification remains unexplored. We describe a chemoproteomic workflow to map and quantify over 1,000 S-sulphenylation sites on more than 700 proteins in intact cells. Quantitative analysis of human cells stimulated with hydrogen peroxide or epidermal growth factor measured hundreds of site selective redox changes. Different cysteines in the same proteins displayed dramatic differences in susceptibility to S-sulphenylation. Newly discovered S-sulphenylations provided mechanistic support for proposed cysteine redox reactions and suggested novel redox mechanisms, including S-sulphenyl-mediated redox regulation of the transcription factor HIF1A by SIRT6. S-sulphenylation is favored at solvent-exposed protein surfaces and is associated with sequence motifs that are distinct from those for other thiol modifications. S-sulphenylations affect regulators of phosphorylation, acetylation and ubiquitylation, which suggest regulatory crosstalk between redox control and signalling pathways.
0 Communities
1 Members
0 Resources
17 MeSH Terms
From wavy hair to naked proteins: the role of transforming growth factor alpha in health and disease.
Singh B, Coffey RJ
(2014) Semin Cell Dev Biol 28: 12-21
MeSH Terms: Animals, EGF Family of Proteins, Epidermal Growth Factor, Epithelial Cells, Hair, Humans, Signal Transduction, Transforming Growth Factor alpha
Show Abstract · Added March 27, 2014
Since its discovery in 1978 and cloning in 1984, transforming growth factor-alpha (TGF-α, TGFA) has been one of the most extensively studied EGF receptor (EGFR) ligands. In this review, we provide a historical perspective on TGFA-related studies, highlighting what we consider important advances related to its function in normal and disease states.
Copyright © 2014 Elsevier Ltd. All rights reserved.
1 Communities
2 Members
0 Resources
8 MeSH Terms
Epidermal growth factor, from gene organization to bedside.
Zeng F, Harris RC
(2014) Semin Cell Dev Biol 28: 2-11
MeSH Terms: Animals, Cell Differentiation, Epidermal Growth Factor, Epithelial Cells, ErbB Receptors, Gene Expression, Humans, Signal Transduction
Show Abstract · Added October 27, 2014
In 1962, epidermal growth factor (EGF) was discovered by Dr. Stanley Cohen while studying nerve growth factor (NGF). It was soon recognized that EGF is the prototypical member of a family of peptide growth factors that activate the EGF receptors, and that the EGF/EGF receptor signaling pathway plays important roles in proliferation, differentiation and migration of a variety of cell types, especially in epithelial cells. After the basic characterization of EGF function in the first decade or so after its discovery, the studies related to EGF and its signaling pathway have extended to a broad range of investigations concerning its biological and pathophysiological roles in development and in human diseases. In this review, we briefly describe the gene organization and tissue distribution of EGF, with emphasis on its biological and pathological roles in human diseases.
Copyright © 2014 Elsevier Ltd. All rights reserved.
1 Communities
1 Members
0 Resources
8 MeSH Terms
Cytokine-driven beta-cell production in vivo.
Worchel HN, Magnuson MA
(2014) Nat Biotechnol 32: 63-4
MeSH Terms: Animals, Ciliary Neurotrophic Factor, Diabetes Mellitus, Epidermal Growth Factor, Insulin-Secreting Cells
Added February 11, 2014
1 Communities
1 Members
0 Resources
5 MeSH Terms
Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice.
Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, Heimberg H
(2014) Nat Biotechnol 32: 76-83
MeSH Terms: Acinar Cells, Animals, Cell Differentiation, Cell Proliferation, Ciliary Neurotrophic Factor, Diabetes Mellitus, Epidermal Growth Factor, Hyperglycemia, Insulin-Secreting Cells, Mice, Mice, Inbred NOD, Signal Transduction
Show Abstract · Added February 3, 2014
Reprogramming of pancreatic exocrine cells into cells resembling beta cells may provide a strategy for treating diabetes. Here we show that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells. Newly generated beta-like cells are epigenetically reprogrammed, functional and glucose responsive, and they reinstate normal glycemic control for up to 248 d. The regenerative process depends on Stat3 signaling and requires a threshold number of Neurogenin 3 (Ngn3)-expressing acinar cells. In contrast to previous work demonstrating in vivo conversion of acinar cells to beta-like cells by viral delivery of exogenous transcription factors, our approach achieves acinar-to-beta-cell reprogramming through transient cytokine exposure rather than genetic modification.
3 Communities
2 Members
0 Resources
12 MeSH Terms
Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis.
Barrett CW, Singh K, Motley AK, Lintel MK, Matafonova E, Bradley AM, Ning W, Poindexter SV, Parang B, Reddy VK, Chaturvedi R, Fingleton BM, Washington MK, Wilson KT, Davies SS, Hill KE, Burk RF, Williams CS
(2013) PLoS One 8: e67845
MeSH Terms: Animals, Azoxymethane, Carcinogenesis, Colitis, Colonic Neoplasms, DNA Damage, Deoxyguanosine, Dextran Sulfate, Diet, Epidermal Growth Factor, Gene Expression Regulation, Inflammation, Mice, Mice, Inbred C57BL, Selenium, Signal Transduction, Transforming Growth Factor beta, Weight Loss
Show Abstract · Added March 5, 2014
Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.
3 Communities
8 Members
0 Resources
18 MeSH Terms
AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve.
Er EE, Mendoza MC, Mackey AM, Rameh LE, Blenis J
(2013) Sci Signal 6: ra45
MeSH Terms: Blotting, Western, Cell Line, Endocytosis, Endosomes, Enzyme Activation, Epidermal Growth Factor, ErbB Receptors, HEK293 Cells, Humans, Lysosomes, Microscopy, Confocal, Models, Biological, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Transport, Proteolysis, Proto-Oncogene Proteins c-akt, RNA Interference, Signal Transduction
Show Abstract · Added November 26, 2018
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that controls cell proliferation, growth, survival, metabolism, and migration by activating the PI3K (phosphatidylinositol 3-kinase)-AKT and ERK (extracellular signal-regulated kinase)-RSK (ribosomal S6 kinase) pathways. EGFR signaling to these pathways is temporally and spatially regulated. Endocytic trafficking controls the access of EGFR to these downstream effectors and also its degradation, which terminates EGFR signaling. We showed that AKT facilitated the endocytic trafficking of EGFR to promote its degradation. Interfering with AKT signaling reduced both EGFR recycling and the rate of EGFR degradation. In AKT-impaired cells, EGFRs were unable to reach the cell surface or the lysosomal compartment and accumulated in the early endosomes, resulting in prolonged signaling and increased activation of ERK and RSK. Upon EGF stimulation, AKT phosphorylated and activated the kinase PIKfyve [FYVE-containing phosphatidylinositol 3-phosphate 5-kinase], which promoted vesicle trafficking to lysosomes. PIKfyve activation promoted EGFR degradation. Similar regulation occurred with platelet-derived growth factor receptor (PDGFR), suggesting that AKT phosphorylation and activation of PIKfyve is likely to be a common feedback mechanism for terminating RTK signaling and reducing receptor abundance.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Transformation of polarized epithelial cells by apical mistrafficking of epiregulin.
Singh B, Bogatcheva G, Washington MK, Coffey RJ
(2013) Proc Natl Acad Sci U S A 110: 8960-5
MeSH Terms: Animals, Cell Polarity, Cell Transformation, Neoplastic, Dogs, Electric Impedance, Electrophoresis, Polyacrylamide Gel, Epidermal Growth Factor, Epiregulin, Epithelial Cells, Fluorescent Antibody Technique, Immunoblotting, Immunoprecipitation, Madin Darby Canine Kidney Cells, Mice, Microscopy, Confocal, Phosphorylation, Protein Transport, Signal Transduction
Show Abstract · Added March 7, 2014
Establishment and maintenance of apico-basolateral trafficking pathways are critical to epithelial homeostasis. Loss of polarity and trafficking fidelity are thought to occur as a consequence of transformation; however, here we report that selective mistrafficking of the epidermal growth factor receptor (EGFR) ligand epiregulin (EREG) from the basolateral to the apical cell surface drives transformation. Normally, EREG is preferentially delivered to the basolateral surface of polarized Madin-Darby canine kidney cells. EREG basolateral trafficking is regulated by a conserved tyrosine-based basolateral sorting motif in its cytoplasmic domain (YXXΦ: Y(156)ERV). Both Y156 and V159 are required for basolateral sorting of EREG, because Y156A and V159G substitutions redirect EREG to the apical cell surface. We also show that basolateral sorting of EREG is adaptor protein 1B-independent. Apical mistrafficking of EREG has a distinctive phenotype. In contrast to transient EGFR tyrosine phosphorylation after basolateral EREG stimulation, apical EREG leads to prolonged EGFR tyrosine phosphorylation, which may be related, at least in part, to a lack of negative regulatory Y1045 phosphorylation and subsequent ubiquitylation. Notably, Madin-Darby canine kidney cells stably expressing apically mistrafficked EREG form significantly larger, hyperproliferative, poorly differentiated, and locally invasive tumors in nude mice compared with WT EREG-expressing cells.
1 Communities
3 Members
0 Resources
18 MeSH Terms