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Flaria El Khoury, Laurent Corcos, Stéphanie Durand, Brigitte Simon, Catherine Le Jossic-Corcos
Colorectal cancer (CRC) is one of the most aggressive cancers worldwide. Several anticancer agents are available to treat CRC, but eventually cancer relapse occurs. One major cause of chemotherapy failure is the emergence of drug-resistant tumor cells, suspected to originate from the stem cell compartment. The aim of this study was to ask whether drug resistance was associated with the acquisition of stem cell-like properties. We isolated drug-resistant derivatives of two human CRC cell lines, HT29 and HCT116, using two anticancer drugs with distinct modes of action, oxaliplatin and docetaxel...
October 7, 2016: International Journal of Oncology
Xiao-Na Zhu, Xian-Dong Liu, Hanyi Zhuang, Mark Henkemeyer, Jing-Yu Yang, Nan-Jie Xu
UNLABELLED: The amygdala serves as emotional center to mediate innate fear behaviors that are reflected through neuronal responses to environmental aversive cues. However, the molecular mechanism underlying the initial neuron responses is poorly understood. In this study, we monitored the innate defensive responses to aversive stimuli of either elevated plus maze or predator odor in juvenile mice and found that glutamatergic neurons were activated in amygdala. Loss of EphB2, a receptor tyrosine kinase expressed in amygdala neurons, suppressed the reactions and led to defects in spine morphogenesis and fear behaviors...
September 28, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Doua F Azzouz, Gabriel V Martin, Fanny Arnoux, Nathalie Balandraud, Thierry Martin, Sylvain Dubucquoi, Eric Hachulla, Dominique Farge-Bancel, Kiet Tiev, Jean Cabane, Nathalie Bardin, Laurent Chiche, Marielle Martin, Eléonore C Caillet, Sami B Kanaan, Jean Robert Harlé, Brigitte Granel, Elisabeth Diot, Jean Roudier, Isabelle Auger, Nathalie C Lambert
In a pilot ProtoArray analysis, we identified 6 proteins out of 9483 recognized by autoantibodies (AAb) from patients with systemic sclerosis (SSc). We further investigated the 6 candidates by ELISA on hundreds of controls and patients, including patients with Systemic Lupus Erythematosus (SLE), known for high sera reactivity and overlapping AAb with SSc. Only 2 of the 6 candidates, Ephrin type-B receptor 2 (EphB2) and Three prime Histone mRNA EXonuclease 1 (THEX1), remained significantly recognized by sera samples from SSc compared to controls (healthy or with rheumatic diseases) with, respectively, 34% versus 14% (P = 2...
2016: PloS One
Thomas N Gaitanos, Jorg Koerner, Ruediger Klein
Ephrin receptors interact with membrane-bound ephrin ligands to regulate contact-mediated attraction or repulsion between opposing cells, thereby influencing tissue morphogenesis. Cell repulsion requires bidirectional trans-endocytosis of clustered Eph-ephrin complexes at cell interfaces, but the mechanisms underlying this process are poorly understood. Here, we identified an actin-regulating pathway allowing ephrinB(+) cells to trans-endocytose EphB receptors from opposing cells. Live imaging revealed Rac-dependent F-actin enrichment at sites of EphB2 internalization, but not during vesicle trafficking...
September 12, 2016: Journal of Cell Biology
Pooja Ghatalia, Eddy S Yang, Brittany N Lasseigne, Ryne C Ramaker, Sara J Cooper, Dongquan Chen, Sunil Sudarshan, Shi Wei, Arjun S Guru, Amy Zhao, Tiffiny Cooper, Deborah L Della Manna, Gurudatta Naik, Richard M Myers, Guru Sonpavde
Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets...
2016: PloS One
Oskar Schnappauf, Sven Beyes, Annika Dertmann, Vivien Freihen, Patrick Frey, Sabine Jägle, Katja Rose, Tom Michoel, Rudolf Grosschedl, Andreas Hecht
Transcriptional silencing is a major cause for the inactivation of tumor suppressor genes, however, the underlying mechanisms are only poorly understood. The EPHB2 gene encodes a receptor tyrosine kinase that controls epithelial cell migration and allocation in intestinal crypts. Through its ability to restrict cell spreading, EPHB2 functions as a tumor suppressor in colorectal cancer whose expression is frequently lost as tumors progress to the carcinoma stage. Previously we reported that EPHB2 expression depends on a transcriptional enhancer whose activity is diminished in EPHB2 non-expressing cells...
August 5, 2016: Biochimica et Biophysica Acta
Sara Ferluga, Carla Maria Lema Tomé, Denise Mazess Herpai, Ralph D'Agostino, Waldemar Debinski
Eph tyrosine kinase receptors are frequently overexpressed and functional in many cancers, and they are attractive candidates for targeted therapy. Here, we analyzed the expression of Eph receptor A3, one of the most up-regulated factors in glioblastoma cells cultured under tumorsphere-forming conditions, together with EphA2 and EphB2 receptors. EphA3 was overexpressed in up to 60% of glioblastoma tumors tested, but not in normal brain. EphA3 was localized in scattered areas of the tumor, the invasive ring, and niches near tumor vessels...
August 1, 2016: Oncotarget
Carrie M Nielson, Ching-Ti Liu, Albert V Smith, Cheryl L Ackert-Bicknell, Sjur Reppe, Johanna Jakobsdottir, Christina Wassel, Thomas C Register, Ling Oei, Nerea Alonso, Edwin H Oei, Neeta Parimi, Elizabeth J Samelson, Mike A Nalls, Joseph Zmuda, Thomas Lang, Mary Bouxsein, Jeanne Latourelle, Melina Claussnitzer, Kristin Siggeirsdottir, Priya Srikanth, Erik Lorentzen, Liesbeth Vandenput, Carl Langefeld, Laura Raffield, Greg Terry, Amanda J Cox, Matthew A Allison, Michael H Criqui, Don Bowden, M Arfan Ikram, Dan Mellström, Magnus K Karlsson, John Carr, Matthew Budoff, Caroline Phillips, L Adrienne Cupples, Wen-Chi Chou, Richard H Myers, Stuart H Ralston, Kaare M Gautvik, Peggy M Cawthon, Steven Cummings, David Karasik, Fernando Rivadeneira, Vilmundur Gudnason, Eric S Orwoll, Tamara B Harris, Claes Ohlsson, Douglas P Kiel, Yi-Hsiang Hsu
Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893)...
August 1, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Sonia Alonso-Martin, Anne Rochat, Despoina Mademtzoglou, Jessica Morais, Aurélien de Reyniès, Frédéric Auradé, Ted Hung-Tse Chang, Peter S Zammit, Frédéric Relaix
Skeletal muscle growth and regeneration require a population of muscle stem cells, the satellite cells, located in close contact to the myofiber. These cells are specified during fetal and early postnatal development in mice from a Pax3/7 population of embryonic progenitor cells. As little is known about the genetic control of their formation and maintenance, we performed a genome-wide chronological expression profile identifying the dynamic transcriptomic changes involved in establishment of muscle stem cells through life, and acquisition of muscle stem cell properties...
2016: Frontiers in Cell and Developmental Biology
Koichiro Suzuki, Takahiro Aimi, Tomoaki Ishihara, Tohru Mizushima
Ephrin type-B receptor 2 (EphB2) is a member of the receptor tyrosine kinase family and plays an important role in learning and memory functions. In patients with Alzheimer's disease (AD) and in mouse models of AD, a reduction in the hippocampal EphB2 level is observed. It was recently reported that normalization of the EphB2 level in the dentate gyrus rescues memory function in a mouse model of AD, suggesting that drugs that restore EphB2 levels may be beneficial in the treatment of AD. Amyloid β (Aβ) oligomers, which are believed to be key molecules involved in the pathogenesis of AD, induce EphB2 degradation through their direct binding to EphB2...
May 2016: FEBS Open Bio
Jesús Planagumà, Holger Haselmann, Francesco Mannara, Mar Petit-Pedrol, Benedikt Grünewald, Esther Aguilar, Luise Röpke, Elena Martín-García, Maarten J Titulaer, Pablo Jercog, Francesc Graus, Rafael Maldonado, Christian Geis, Josep Dalmau
OBJECTIVE: To demonstrate that ephrin-B2 (the ligand of EphB2 receptor) antagonizes the pathogenic effects of patients' N-methyl-D-aspartate receptor (NMDAR) antibodies on memory and synaptic plasticity. METHODS: One hundred twenty-two C57BL/6J mice infused with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, with or without ephrin-B2, were investigated. CSF was infused through ventricular catheters connected to subcutaneous osmotic pumps over 14 days...
September 2016: Annals of Neurology
Huanhuan Joyce Chen, Zhubo Wei, Jian Sun, Asmita Bhattacharya, David J Savage, Rita Serda, Yuri Mackeyev, Steven A Curley, Pengcheng Bu, Lihua Wang, Shuibing Chen, Leona Cohen-Gould, Emina Huang, Xiling Shen, Steven M Lipkin, Neal G Copeland, Nancy A Jenkins, Michael L Shuler
Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia...
August 2016: Nature Biotechnology
Elena B Pasquale
Membrane-anchored Eph receptors and ephrins represent a ubiquitous intercellular communication system that typically engages at sites of cell-cell contact to initiate bidirectional signaling. Gong et al. (2016. J. Cell Biol. show that cells can deploy the EphB2 receptor on exosomes to activate ephrinB signaling and collapse the growth cones of distant neurons.
July 4, 2016: Journal of Cell Biology
Jingyi Gong, Roman Körner, Louise Gaitanos, Rüdiger Klein
The cellular release of membranous vesicles known as extracellular vesicles (EVs) or exosomes represents a novel mode of intercellular communication. Eph receptor tyrosine kinases and their membrane-tethered ephrin ligands have very important roles in such biologically diverse processes as neuronal development, plasticity, and pathological diseases. Until now, it was thought that ephrin-Eph signaling requires direct cell contact. Although the biological functions of ephrin-Eph signaling are well understood, our mechanistic understanding remains modest...
July 4, 2016: Journal of Cell Biology
Jessica Lauriol, Janel R Cabrera, Ashbeel Roy, Kimberly Keith, Sara M Hough, Federico Damilano, Bonnie Wang, Gabriel C Segarra, Meaghan E Flessa, Lauren E Miller, Saumya Das, Roderick Bronson, Kyu-Ho Lee, Maria I Kontaridis
Hypertrophic cardiomyopathy is a common cause of mortality in congenital heart disease (CHD). Many gene abnormalities are associated with cardiac hypertrophy, but their function in cardiac development is not well understood. Loss-of-function mutations in PTPN11, which encodes the protein tyrosine phosphatase (PTP) SHP2, are implicated in CHD and cause Noonan syndrome with multiple lentigines (NSML), a condition that often presents with cardiac hypertrophic defects. Here, we found that NSML-associated hypertrophy stems from aberrant signaling mechanisms originating in developing endocardium...
August 1, 2016: Journal of Clinical Investigation
Christiane Peuckert, Bejan Aresh, Pavlo Holenya, Derek Adams, Smitha Sreedharan, Annika Porthin, Louise Andersson, Hanna Pettersson, Stefan Wölfl, Rüdiger Klein, Leif Oxburgh, Klas Kullander
A substantial portion of the human population is affected by urogenital birth defects resulting from a failure in ureter development. Although recent research suggests roles for several genes in facilitating the ureter/bladder connection, the underlying molecular mechanisms remain poorly understood. Signaling via Eph receptor tyrosine kinases is involved in several developmental processes. Here we report that impaired Eph/Ephrin signaling in genetically modified mice results in severe hydronephrosis caused by defective ureteric bud induction, ureter maturation, and translocation...
August 2016: Kidney International
Man-Hong Keung, Lai-Sheung Chan, Hoi-Hin Kwok, Ricky Ngok-Shun Wong, Patrick Ying-Kit Yue
BACKGROUND: Ginsenoside-Rg3, the pharmacologically active component of red ginseng, has been found to inhibit tumor growth, invasion, metastasis, and angiogenesis in various cancer models. Previously, we found that 20(R)-ginsenoside-Rg3 (Rg3) could inhibit angiogenesis. Since microRNAs (miRNAs) have been shown to affect many biological processes, they might play an important role in ginsenoside-mediated angiomodulation. METHODS: In this study, we examined the underlying mechanisms of Rg3-induced angiosuppression through modulating the miRNA expression...
April 2016: Journal of Ginseng Research
Sofia Huroy, Ashlin Kanawaty, Lilia Magomedova, Carolyn L Cummins, Susan R George, Derek van der Kooy, Jeffrey T Henderson
No abstract text is available yet for this article.
April 28, 2016: Behavioural Brain Research
Nelly Noraz, Iness Jaaoini, Camille Charoy, Chantal Watrin, Naura Chounlamountri, Aurélien Benon, Céline Malleval, Hélène Boudin, Jérôme Honnorat, Valérie Castellani, Véronique Pellier-Monnin
In the hematopoietic system, Syk family tyrosine kinases are essential components of immunoreceptor ITAM-based signaling. While there is increasing data indicating the involvement of immunoreceptors in neural functions, the contribution of Syk kinases remains obscure. Previously, we identified phosphorylated forms of Syk kinases in specialized populations of migrating neurons or projecting axons. Moreover, we identified ephrin/Eph as guidance molecules utilizing the ITAM-bearing CD3zeta (Cd247) and associated Syk kinases for the growth cone collapse response induced in vitro Here, we show that in the developing spinal cord, Syk is phosphorylated in navigating commissural axons...
June 15, 2016: Development
Ruo-Xi Zhang, Ying Han, Chen Chen, Ling-Zhi Xu, Jia-Li Li, Na Chen, Cheng-Yu Sun, Wen-Hao Chen, Wei-Li Zhu, Jie Shi, Lin Lu
The ephrin B2 (EphB2) receptor is a tyrosine kinase receptor that is associated with synaptic development and maturation. It has recently been implicated in cognitive deficits and anxiety. However, still unknown is the involvement of EphB2 in the vulnerability to stress. In the present study, we observed decreases in EphB2 levels and their downstream molecules in the medial prefrontal cortex (mPFC) but not in the orbitofrontal cortex (OFC) in mice that were susceptible to chronic social defeat stress. The activation of EphB2 receptors with EphrinB1-Fc in the mPFC produced stress-resistant and antidepressant-like behavioral effects in susceptible mice that lasted for at least 10 days...
September 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
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