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Results: 1 to 10 of 25

Publication Record


Induction of lateral lumens through disruption of a monoleucine-based basolateral-sorting motif in betacellulin.
Singh B, Bogatcheva G, Starchenko A, Sinnaeve J, Lapierre LA, Williams JA, Goldenring JR, Coffey RJ
(2015) J Cell Sci 128: 3444-55
MeSH Terms: Amino Acid Sequence, Animals, Betacellulin, Cell Polarity, Dogs, EGF Family of Proteins, ErbB Receptors, Fluorescent Antibody Technique, Madin Darby Canine Kidney Cells, Mutation, Protein Sorting Signals, Protein Structure, Tertiary
Show Abstract · Added September 28, 2015
Directed delivery of EGF receptor (EGFR) ligands to the apical or basolateral surface is a crucial regulatory step in the initiation of EGFR signaling in polarized epithelial cells. Herein, we show that the EGFR ligand betacellulin (BTC) is preferentially sorted to the basolateral surface of polarized MDCK cells. By using sequential truncations and site-directed mutagenesis within the BTC cytoplasmic domain, combined with selective cell-surface biotinylation and immunofluorescence, we have uncovered a monoleucine-based basolateral-sorting motif (EExxxL, specifically (156)EEMETL(161)). Disruption of this sorting motif led to equivalent apical and basolateral localization of BTC. Unlike other EGFR ligands, BTC mistrafficking induced formation of lateral lumens in polarized MDCK cells, and this process was significantly attenuated by inhibition of EGFR. Additionally, expression of a cancer-associated somatic BTC mutation (E156K) led to BTC mistrafficking and induced lateral lumens in MDCK cells. Overexpression of BTC, especially mistrafficking forms, increased the growth of MDCK cells. These results uncover a unique role for BTC mistrafficking in promoting epithelial reorganization.
© 2015. Published by The Company of Biologists Ltd.
0 Communities
4 Members
0 Resources
12 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
Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-α: impact on gastrointestinal cancers driven by secondary bile acids.
Nagathihalli NS, Beesetty Y, Lee W, Washington MK, Chen X, Lockhart AC, Merchant NB
(2014) Cancer Res 74: 2062-72
MeSH Terms: ADAM Proteins, ADAM17 Protein, Amphiregulin, Bile Acids and Salts, Cyclin D1, Deoxycholic Acid, EGF Family of Proteins, ErbB Receptors, Gastrointestinal Neoplasms, Glycoproteins, HCT116 Cells, Humans, Intercellular Signaling Peptides and Proteins, Pancreas, Phosphorylation, Receptors, G-Protein-Coupled, STAT3 Transcription Factor, Transforming Growth Factor alpha, src-Family Kinases
Show Abstract · Added February 14, 2014
Secondary bile acids (BA) such as deoxycholic acid (DCA) promote the development of several gastrointestinal malignancies, but how they mediate this effect is unclear. In this study, we offer evidence of a mechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α, which rely upon the cell surface protease TACE/ADAM-17. Specifically, we show that AREG participates in DCA-induced EGFR and STAT3 signaling, cell-cycle progression, and tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). TACE and AREG, but not TGF-α, were overexpressed in both colorectal cancer and PDAC tissues compared with normal tissues. Exposure of colorectal cancer and PDAC cells to DCA resulted in colocalization of Src and TACE to the cell membrane, resulting in AREG-dependent activation of EGFR, mitogen-activated protein kinase (MAPK), and STAT3 signaling. Src or TACE inhibition was sufficient to attenuate DCA-induced AREG, but not TGF-α shedding. We also examined a role for the BA transporter TGR5 in DCA-mediated EGFR and STAT3 signaling. RNA interference-mediated silencing of TGR5 or AREG inhibited DCA-induced EGFR, MAPK, and STAT3 signaling, blunted cyclin D1 expression and cell-cycle progression, and attenuated DCA-induced colorectal cancer or PDAC tumorigenicity. Together, our findings define an AREG-dependent signaling pathway that mediates the oncogenic effects of secondary BAs in gastrointestinal cancers, the targeting of which may enhance therapeutic responses in their treatment.
©2014 AACR.
0 Communities
3 Members
0 Resources
19 MeSH Terms
Myofibroblast keratinocyte growth factor reduces tight junctional integrity and increases claudin-2 levels in polarized Caco-2 cells.
Kim TI, Poulin EJ, Blask E, Bukhalid R, Whitehead RH, Franklin JL, Coffey RJ
(2012) Growth Factors 30: 320-32
MeSH Terms: Amphiregulin, Caco-2 Cells, Cell Communication, Cell Line, Tumor, Cell Membrane Permeability, Cell Proliferation, Claudin-2, Culture Media, Conditioned, EGF Family of Proteins, Electric Impedance, ErbB Receptors, Fibroblast Growth Factor 7, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Intestinal Mucosa, Ligands, Myofibroblasts, Tight Junctions
Show Abstract · Added December 5, 2013
The colonic epithelium is composed of a polarized monolayer sheathed by a layer of pericryptal myofibroblasts (PCMFs). We mimicked these cellular compartments in vitro to assess the effects of paracrine-acting PCMF-derived factors on tight junction (TJ) integrity, as measured by transepithelial electrical resistance (TER). Coculture with 18Co PCMFs, or basolateral administration of 18Co conditioned medium, significantly reduced TER of polarized Caco-2 cells. Among candidate paracrine factors, only keratinocyte growth factor (KGF) reduced Caco-2 TER; basolateral KGF treatment led to time- and concentration-dependent increases in claudin-2 levels. We also demonstrate that amphiregulin (AREG), produced largely by Caco-2 cells, increased claudin-2 levels, leading to epidermal growth factor receptor-mediated TER reduction. We propose that colonic epithelial TJ integrity can be modulated by paracrine KGF and autocrine AREG through increased claudin-2 levels. KGF-regulated claudin-2 induction may have implications for inflammatory bowel disease, where both KGF and claudin-2 are upregulated.
2 Communities
2 Members
0 Resources
19 MeSH Terms
Identification of a novel mono-leucine basolateral sorting motif within the cytoplasmic domain of amphiregulin.
Gephart JD, Singh B, Higginbotham JN, Franklin JL, Gonzalez A, Fölsch H, Coffey RJ
(2011) Traffic 12: 1793-804
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Amphiregulin, Animals, Cell Line, Cell Membrane, Cell Polarity, Cytoplasm, Dogs, EGF Family of Proteins, Epithelial Cells, ErbB Receptors, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, LLC-PK1 Cells, Leucine, Membrane Proteins, Molecular Sequence Data, Protein Structure, Tertiary, Protein Transport, Receptors, Nerve Growth Factor, Swine
Show Abstract · Added December 5, 2013
Epithelial cells establish apical and basolateral (BL) membranes with distinct protein and lipid compositions. To achieve this spatial asymmetry, the cell utilizes a variety of mechanisms for differential sorting, delivery and retention of cell surface proteins. The EGF receptor (EGFR) and its ligand, amphiregulin (AREG), are transmembrane proteins delivered to the BL membrane in polarized epithelial cells. Herein, we show that the cytoplasmic domain of AREG (ACD) contains dominant BL sorting information; replacement of the cytoplasmic domain of apically targeted nerve growth factor receptor with the ACD redirects the chimera to the BL surface. Using sequential truncations and site-directed mutagenesis of the ACD, we identify a novel BL sorting motif consisting of a single leucine C-terminal to an acidic cluster (EEXXXL). In adaptor protein (AP)-1B-deficient cells, newly synthesized AREG is initially delivered to the BL surface as in AP-1B-expressing cells. However, in these AP-1B-deficient cells, recycling of AREG back to the BL surface is compromised, leading to its appearance at the apical surface. These results show that recycling, but not delivery, of AREG to the BL surface is AP-1B dependent.
© 2011 John Wiley & Sons A/S.
2 Communities
3 Members
0 Resources
23 MeSH Terms
Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue.
Pasic L, Eisinger-Mathason TS, Velayudhan BT, Moskaluk CA, Brenin DR, Macara IG, Lannigan DA
(2011) Genes Dev 25: 1641-53
MeSH Terms: Amphiregulin, Animals, Apoptosis, Bacterial Capsules, Cell Differentiation, Cell Proliferation, Cells, Cultured, EGF Family of Proteins, Epidermal Growth Factor, Epithelial Cells, ErbB Receptors, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Mammary Glands, Human, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Receptor, Fibroblast Growth Factor, Type 2, Ribosomal Protein S6 Kinases, 90-kDa, Signal Transduction
Show Abstract · Added March 5, 2014
Human mammary glands arise from multipotent progenitor cells, which likely respond both to cell-autonomous and to extrinsic cues. However, the identity of these cues and how they might act remain unclear. We analyzed HER1 ligand effects on mammary morphogenesis using a three-dimensional organoid model generated from human breast tissue that recapitulates both qualitatively and quantitatively the normal ductal network in situ. Strikingly, different HER1 ligands generate distinct patterns of cell fate. Epidermal growth factor (EGF) causes a massive expansion of the myoepithelial lineage. Amphiregulin, in contrast, enables normal ductal development. These differences cannot be ascribed to preferential apoptosis or proliferation of differentiated cell populations, but are dependent on HER1 signal intensity. Inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) effector RSK prevents the EGF-induced myoepithelial expansion. Notably, mouse mammary organoids are much less responsive to HER1 ligands. Little is known about the myoepithelial lineage or about growth factor effects on mammary progenitor differentiation, and our studies provide an important window into human mammary development that reveals unexpected differences from the mouse model.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Amphiregulin exosomes increase cancer cell invasion.
Higginbotham JN, Demory Beckler M, Gephart JD, Franklin JL, Bogatcheva G, Kremers GJ, Piston DW, Ayers GD, McConnell RE, Tyska MJ, Coffey RJ
(2011) Curr Biol 21: 779-86
MeSH Terms: Amphiregulin, Animals, Cell Line, Tumor, Centrifugation, Dogs, EGF Family of Proteins, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, ErbB Receptors, Exosomes, Glycoproteins, Heparin-binding EGF-like Growth Factor, Humans, Immunoblotting, Intercellular Signaling Peptides and Proteins, Microscopy, Electron, Neoplasm Invasiveness, Signal Transduction, Transforming Growth Factor alpha
Show Abstract · Added December 6, 2012
Autocrine, paracrine, and juxtacrine are recognized modes of action for mammalian EGFR ligands including EGF, TGF-α (TGFα), amphiregulin (AREG), heparin-binding EGF-like growth factor (HB-EGF), betacellulin, epiregulin, and epigen. We identify a new mode of EGFR ligand signaling via exosomes. Human breast and colorectal cancer cells release exosomes containing full-length, signaling-competent EGFR ligands. Exosomes isolated from MDCK cells expressing individual full-length EGFR ligands displayed differential activities; AREG exosomes increased invasiveness of recipient breast cancer cells 4-fold over TGFα or HB-EGF exosomes and 5-fold over equivalent amounts of recombinant AREG. Exosomal AREG displayed significantly greater membrane stability than TGFα or HB-EGF. An average of 24 AREG molecules are packaged within an individual exosome, and AREG exosomes are rapidly internalized by recipient cells. Whether the composition and behavior of exosomes differ between nontransformed and transformed cells is unknown. Exosomes from DLD-1 colon cancer cells with a mutant KRAS allele exhibited both higher AREG levels and greater invasive potential than exosomes from isogenically matched, nontransformed cells in which mutant KRAS was eliminated by homologous recombination. We speculate that EGFR ligand signaling via exosomes might contribute to diverse cancer phenomena such as field effect and priming of the metastatic niche.
Copyright © 2011 Elsevier Ltd. All rights reserved.
2 Communities
5 Members
0 Resources
19 MeSH Terms
Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.
Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A, Koutcher JA, Spassova M, Ouerfelli O, Mellinghoff IK, Zakowski MF, Politi KA, Pao W
(2009) J Clin Invest 119: 3000-10
MeSH Terms: Afatinib, Amphiregulin, Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Cetuximab, Disease Models, Animal, Drug Resistance, Neoplasm, EGF Family of Proteins, Epidermal Growth Factor, Epiregulin, ErbB Receptors, Erlotinib Hydrochloride, Gene Expression Profiling, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Lung Neoplasms, Male, Mice, Mice, Nude, Mice, Transgenic, Mutation, Neoplasm Transplantation, Paclitaxel, Protein Kinase Inhibitors, Quinazolines, Transplantation, Heterologous, Tumor Cells, Cultured
Show Abstract · Added March 24, 2014
EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas characterized by mutations in exons encoding the EGFR tyrosine kinase domain, but disease progression invariably occurs. A major reason for such acquired resistance is the outgrowth of tumor cells with additional TKI-resistant EGFR mutations. Here we used relevant transgenic mouse lung tumor models to evaluate strategies to overcome the most common EGFR TKI resistance mutation, T790M. We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab. Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance. Moreover, this approach could serve as an important model for targeting other receptor tyrosine kinases activated in human cancers.
0 Communities
1 Members
0 Resources
30 MeSH Terms
Amphiregulin-deficient mice develop spasmolytic polypeptide expressing metaplasia and intestinal metaplasia.
Nam KT, Lee HJ, Mok H, Romero-Gallo J, Crowe JE, Peek RM, Goldenring JR
(2009) Gastroenterology 136: 1288-96
MeSH Terms: Amphiregulin, Animals, Cell Proliferation, Disease Models, Animal, EGF Family of Proteins, Gastric Fundus, Gastric Mucosa, Genetic Predisposition to Disease, Glycoproteins, Intercellular Signaling Peptides and Proteins, Intestinal Mucosa, Intestines, Metaplasia, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucin-2, Mucins, Muscle Proteins, Peptides, Stomach, Stomach Neoplasms, Transforming Growth Factor alpha, Trefoil Factor-2, Trefoil Factor-3, beta Catenin
Show Abstract · Added October 7, 2013
BACKGROUND & AIMS - The loss of parietal cells from the fundic mucosa leads to the emergence of metaplastic lineages associated with an increased susceptibility to neoplastic transformation. Both intestinal metaplasia (IM) and spasmolytic polypeptide (TFF2/SP) expressing metaplasia (SPEM) have been identified in human stomach, but only SPEM is present in most mouse models of gastric metaplasia. We previously determined that loss of amphiregulin (AR) promotes SPEM induced by acute oxyntic atrophy. We have now examined whether SPEM in the AR-/- mouse predisposes the stomach to gastric neoplasia.
METHODS - Gross pathology of 18-month-old wild-type, AR-/-, and TGF-alpha-/- mice were examined. Ki-67, beta-catenin, Pdx-1, TFF3, and TFF2/SP expression was analyzed by immunohistochemistry. Metaplastic gastric mucosa was analyzed by dual immunostaining for TFF2/SP with MUC2 or TFF3.
RESULTS - By 18 months of age, more than 70% of AR-/- mice developed SPEM while 42% showed goblet cell IM labeled with MUC2, TFF3, and Pdx-1. A total of 28% had invasive gastric lesions in the fundus. No antral abnormalities were observed in AR-/- mice. Metaplastic cell lineages in AR-/- mice showed increases in cell proliferation and cytosolic beta-catenin expression. Dual staining for TFF2/SP with MUC2 or TFF3 showed glands containing both SPEM and IM with intervening cells expressing both TFF2/SP and MUC2 or TFF2/SP and TFF3.
CONCLUSIONS - AR-/- mice develop SPEM, which gives rise to goblet cell IM and invasive fundic dysplastic lesions. The AR-/- mouse represents the first mouse model for spontaneous development of fundic SPEM with progression to IM.
1 Communities
3 Members
0 Resources
26 MeSH Terms
TACE/ADAM-17: a component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer.
Merchant NB, Voskresensky I, Rogers CM, Lafleur B, Dempsey PJ, Graves-Deal R, Revetta F, Foutch AC, Rothenberg ML, Washington MK, Coffey RJ
(2008) Clin Cancer Res 14: 1182-91
MeSH Terms: ADAM Proteins, ADAM17 Protein, Amphiregulin, Apoptosis, Blotting, Western, Cell Line, Tumor, Colorectal Neoplasms, EGF Family of Proteins, Enzyme Inhibitors, ErbB Receptors, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Tissue Array Analysis, Transforming Growth Factor alpha
Show Abstract · Added August 12, 2010
PURPOSE - Activation of the epidermal growth factor receptor (EGFR) requires cell surface cleavage of EGFR ligands, uptake of soluble ligand by the receptor, and initiation of EGFR tyrosine kinase activity. We define these collective events as the EGFR axis. Transforming growth factor-alpha (TGF-alpha) and amphiregulin are two EGFR ligands that are delivered preferentially to the basolateral surface of polarized epithelial cells where the EGFR resides. TACE/ADAM-17 (tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloprotease) has been implicated in ectodomain cleavage of TGF-alpha and amphiregulin.
EXPERIMENTAL DESIGN - Using a human polarizing colorectal cancer (CRC) cell line, HCA-7, and a tissue array of normal colonic mucosa and primary and metastatic CRC, we determined the intracellular localization of TACE and the effects of EGFR axis inhibition in CRC.
RESULTS - Herein, we show that TACE is localized to the basolateral plasma membrane of polarized HCA-7 cells. TACE is overexpressed in primary and metastatic CRC tumors compared with normal colonic mucosa; the intensity of its immunoreactivity is inversely correlated with that of TGF-alpha and amphiregulin. Pharmacologic blockade of HCA-7 cells with an EGFR monoclonal antibody, a selective EGFR tyrosine kinase inhibitor, and a selective TACE inhibitor results in concentration-dependent decreases in cell proliferation and active, phosphorylated mitogen-activated protein kinase. Combining suboptimal concentrations of these agents results in cooperative growth inhibition, increased apoptosis, and reduced mitogen-activated protein kinase pathway activation. Furthermore, an EGFR tyrosine kinase-resistant clone of HCA-7 cells is growth-inhibited by combined monoclonal antibody and TACE inhibition.
CONCLUSION - These results implicate TACE as a promising target of EGFR axis inhibition in CRC.
1 Communities
3 Members
0 Resources
15 MeSH Terms