Ephrin-A1 Expression Contributes to the Malignant Characteristics of A
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Ephrin-A Binding and Epha Receptor Expression Delineate the Matrix Compartment of the Striatum
The Journal of Neuroscience, June 15, 1999, 19(12):4962–4971 Ephrin-A Binding and EphA Receptor Expression Delineate the Matrix Compartment of the Striatum L. Scott Janis, Robert M. Cassidy, and Lawrence F. Kromer Department of Cell Biology and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20007 The striatum integrates limbic and neocortical inputs to regulate matrix neurons. In situ hybridization for EphA RTKs reveals that sensorimotor and psychomotor behaviors. This function is de- the two different ligand binding patterns strictly match pendent on the segregation of striatal projection neurons into the mRNA expression patterns of EphA4 and EphA7. anatomical and functional components, such as the striosome Ligand–receptor binding assays indicate that ephrin-A1 and and matrix compartments. In the present study the association ephrin-A4 selectively bind EphA4 but not EphA7 in the lysates of ephrin-A cell surface ligands and EphA receptor tyrosine of striatal tissue. Conversely, ephrin-A2, ephrin-A3, and kinases (RTKs) with the organization of these compartments ephrin-A5 bind EphA7 but not EphA4. These observations im- was determined in postnatal rats. Ephrin-A1 and ephrin-A4 plicate selective interactions between ephrin-A molecules and selectively bind to EphA receptors on neurons restricted to the EphA RTKs as potential mechanisms for regulating the com- matrix compartment. Binding is absent from the striosomes, partmental organization of the striatum. which were identified by m-opioid -
Inhibition of Metastasis by HEXIM1 Through Effects on Cell Invasion and Angiogenesis
Oncogene (2013) 32, 3829–3839 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc ORIGINAL ARTICLE Inhibition of metastasis by HEXIM1 through effects on cell invasion and angiogenesis W Ketchart1, KM Smith2, T Krupka3, BM Wittmann1,7,YHu1, PA Rayman4, YQ Doughman1, JM Albert5, X Bai6, JH Finke4,YXu2, AA Exner3 and MM Montano1 We report on the role of hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1) as an inhibitor of metastasis. HEXIM1 expression is decreased in human metastatic breast cancers when compared with matched primary breast tumors. Similarly we observed decreased expression of HEXIM1 in lung metastasis when compared with primary mammary tumors in a mouse model of metastatic breast cancer, the polyoma middle T antigen (PyMT) transgenic mouse. Re-expression of HEXIM1 (through transgene expression or localized delivery of a small molecule inducer of HEXIM1 expression, hexamethylene-bis-acetamide) in PyMT mice resulted in inhibition of metastasis to the lung. Our present studies indicate that HEXIM1 downregulation of HIF-1a protein allows not only for inhibition of vascular endothelial growth factor-regulated angiogenesis, but also for inhibition of compensatory pro- angiogenic pathways and recruitment of bone marrow-derived cells (BMDCs). Another novel finding is that HEXIM1 inhibits cell migration and invasion that can be partly attributed to decreased membrane localization of the 67 kDa laminin receptor, 67LR, and inhibition of the functional interaction of 67LR with laminin. Thus, HEXIM1 re-expression in breast cancer has therapeutic advantages by simultaneously targeting more than one pathway involved in angiogenesis and metastasis. Our results also support the potential for HEXIM1 to indirectly act on multiple cell types to suppress metastatic cancer. -
Rabbit Anti-Ephrin-A1 Rabbit Anti-Ephrin-A1
Qty: 100 µg/400 µl Rabbit anti-ephrin-A1 Catalog No. 34-3300 Lot No. See product label Rabbit anti-ephrin-A1 FORM This polyclonal antibody is supplied as a 400 µl aliquot at a concentration of 0.25 mg/ml in phosphate buffered saline (pH 7.4) containing 0.1% sodium azide. The antibody is epitope-affinity-purified from rabbit antiserum. PAD: ZMD.39 IMMUNOGEN Synthetic peptide derived from the C-terminal end of mouse ephrin-A1 protein. SPECIFICITY This antibody is specific for the ephrin-A1 protein. REACTIVITY Reactivity is confirmed with a chimeric protein consisting of the extracellular domain of mouse ephrin-A1 and the Fc region of human IgG1. Cross-reactivity with human ephrin-A1 is confirmed with IHC experiments on human tissue sections and this reactivity was expected because of the 85% shared amino acid identity in the extracellular domain. Sample Western Immunoprecipitation Immunohistochemistry Blotting (FFPE) Mouse +++ +++ NT Human NT NT ++ (Excellent +++, Good++, Poor +, No reactivity 0, Not tested NT) USAGE Working concentrations for specific applications should be determined by the investigator. Appropriate concentrations will be affected by several factors, including secondary antibody affinity, antigen concentration, sensitivity of detection method, temperature and length of incubations, etc. The suitability of this antibody for applications other than those listed below has not been determined. The following concentration ranges are recommended starting points for this product. Western Blotting: 1-5 µg/mL Immunoprecipitation: 5-10 µg/ IP reaction Immunohistochemistry: 4-10 µg/mL Please note that immunohistochemical assays were optimized on formalin-fixed, paraffin-embedded tissue sections and Heat Induced Epitope Retrieval (HIER) with EDTA, pH 8.0 was required for optimal staining. -
Eph Receptor Signalling: from Catalytic to Non-Catalytic Functions
Oncogene (2019) 38:6567–6584 https://doi.org/10.1038/s41388-019-0931-2 REVIEW ARTICLE Eph receptor signalling: from catalytic to non-catalytic functions 1,2 1,2 3 1,2 1,2 Lung-Yu Liang ● Onisha Patel ● Peter W. Janes ● James M. Murphy ● Isabelle S. Lucet Received: 20 March 2019 / Revised: 23 July 2019 / Accepted: 24 July 2019 / Published online: 12 August 2019 © The Author(s) 2019. This article is published with open access Abstract Eph receptors, the largest subfamily of receptor tyrosine kinases, are linked with proliferative disease, such as cancer, as a result of their deregulated expression or mutation. Unlike other tyrosine kinases that have been clinically targeted, the development of therapeutics against Eph receptors remains at a relatively early stage. The major reason is the limited understanding on the Eph receptor regulatory mechanisms at a molecular level. The complexity in understanding Eph signalling in cells arises due to following reasons: (1) Eph receptors comprise 14 members, two of which are pseudokinases, EphA10 and EphB6, with relatively uncharacterised function; (2) activation of Eph receptors results in dimerisation, oligomerisation and formation of clustered signalling centres at the plasma membrane, which can comprise different combinations of Eph receptors, leading to diverse downstream signalling outputs; (3) the non-catalytic functions of Eph receptors have been overlooked. This review provides a structural perspective of the intricate molecular mechanisms that 1234567890();,: 1234567890();,: drive Eph receptor signalling, and investigates the contribution of intra- and inter-molecular interactions between Eph receptors intracellular domains and their major binding partners. We focus on the non-catalytic functions of Eph receptors with relevance to cancer, which are further substantiated by exploring the role of the two pseudokinase Eph receptors, EphA10 and EphB6. -
(12) Patent Application Publication (10) Pub. No.: US 2016/0052982 A1 Cohen Et Al
US 2016.0052982A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0052982 A1 Cohen et al. (43) Pub. Date: Feb. 25, 2016 (54) METHODS AND SYSTEMIS FOR DESIGNING Related U.S. Application Data AND/OR CHARACTERIZING SOLUBLE (60) Provisional application No. 61/813,835, filed on Apr. LPIDATED LGAND AGENTS 19, 2013, provisional application No. 61/811.249, filed on Apr. 12, 2013. (71) Applicants: TUFTS MEDICAL CENTER, Boston, Publication Classification MA (US); TRUSTEES OF TUFTS COLLEGE, Medford, MA (US) (51) Int. C. C07K 4/47 (2006.01) (72) Inventors: Charles Cohen, Weston, MA (US); C07K 7/06 (2006.01) Krishna Kumar, Cambridge, MA (US); C07K 7/08 (2006.01) Jamie Raudensky Doyle, Newton, MA GOIN33/50 (2006.01) (52) U.S. C. (US); Alan S. Kopin, Wellesley, MA CPC ........ C07K 14/4703 (2013.01); G0IN33/5023 (US) (2013.01); C07K 7/06 (2013.01); C07K 7/08 (2013.01); A61 K38/00 (2013.01) (21) Appl. No.: 14/783,489 (57) ABSTRACT (22) PCT Fled: Mar. 13, 2014 The present application provides methods for preparing soluble lipidated ligandagents comprising a ligand entity and (86) PCT NO.: PCT/US2O14/026.662 a lipid entity, and in some embodiments, provides relevant parameters of each of these components, thereby enabling S371 (c)(1), appropriate selection of components to assemble active (2) Date: Oct. 9, 2015 agents for any given target of interest. Patent Application Publication Feb. 25, 2016 Sheet 1 of 13 US 2016/0052982 A1 hita CKR wM S-C& 8-5 wn S-88 - Sif the saxes ..? s ligard, log(N) Riotse CXR wha S-C8 &S-Sf e S-882. -
Spatio-Mechanical Epha2/Ephrin-A1 Signaling in Cancer Cells by Qian
Spatio-mechanical EphA2/ephrin-A1 Signaling in Cancer Cells by Qian Xu A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Biophysics in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Jay T. Groves, Chair Professor John Kuriyan Professor Jan Liphardt Professor Kunxin Luo Spring 2011 Spatio-mechanical EphA2/ephrin-A1 Signaling in Cancer Cells Copyright 2011 By Qian Xu 1 Abstract Spatio-mechanical EphA2/ephrin-A1 Signaling in Cancer Cells by Qian Xu Doctor of Philosophy in Biophysics University of California, Berkeley Professor Jay T. Groves, Chair Communication strategies in nature are an integral part to the survival of multi-cellular organisms. Cell membranes provide the chemical environment in which intercellular signaling begins. The vast complexity of this signaling requires that a relatively conserved set of chemical constituents be able to generate enormous signal diversity. Spatial sorting of signaling molecules within the membrane allows for this diversity. My research uses synthetic lipid membranes, solid-state nanostructures, and high-resolution imaging to study a potentially novel spatio- mechanical regulatory mechanism in the EphA2 signaling pathway. My hypothesis is that the multi-scale organization of the EphA2 receptor in the cell membrane regulates its biochemical function. This hypothesis is motivated by the idea that extracellular mechanical inputs have an important role in intracellular signaling cascades. i 1 -
Epha Kinase Activation Regulates HGF-Induced Epithelial Branching
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central JCBArticle EphA kinase activation regulates HGF-induced epithelial branching morphogenesis Hui Miao,1 Christian H. Nickel,2 Lloyd G. Cantley,2 Leslie A. Bruggeman,1 Laura N. Bennardo,1 and Bingcheng Wang1 1Rammelkamp Center for Research, MetroHealth Campus, and Department of Pharmacology and Ireland Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44109 2School of Medicine, Yale University, New Haven, CT 06520 ph kinases and their ephrin ligands are widely expressed Ephrin-A1 inhibited basal ERK1/2 mitogen-activated protein in epithelial cells in vitro and in vivo. Our results show kinase activity; however, the ephrin-A1 effect on cell Ethat activation of endogenous EphA kinases in Madin- protrusion was independent of the mitogen-activated Darby canine kidney (MDCK) cells negatively regulates protein kinase pathway. Ephrin-A1 suppressed HGF-induced hepatocyte growth factor/scatter factor (HGF)–induced activation of Rac1 and p21-activated kinase, whereas RhoA branching morphogenesis in collagen gel. Cotreatment with activation was retained, leading to the preservation of stress HGF and ephrin-A1 reduced sprouting of cell protrusions, fibers. Moreover, dominant-negative RhoA or inhibitor of an early step in branching morphogenesis. Moreover, Rho-associated kinase (Y27632) substantially negated the addition of ephrin-A1 after HGF stimulation resulted in inhibitory effects of ephrin-A1. These data suggest that collapse and retraction of preexisting cell protrusions. In interfering with c-Met signaling to Rho GTPases represents a newly developed assay that simulates the localized inter- a major mechanism by which EphA kinase activation inhibits actions between Ephs and ephrins in vivo, immobilized HGF-induced MDCK branching morphogenesis. -
Epha2 and EGFR: Friends in Life, Partners in Crime
cancers Review EphA2 and EGFR: Friends in Life, Partners in Crime. Can EphA2 Be a Predictive Biomarker of Response to Anti-EGFR Agents? Mario Cioce 1,* and Vito Michele Fazio 1,2,3,* 1 Laboratory of Molecular Medicine and Biotechnology, Department of Medicine, University Campus Bio-Medico of Rome, 00128 Rome, Italy 2 Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy 3 Institute of Translational Pharmacology, National Research Council of Italy (CNR), 00133 Rome, Italy * Correspondence: [email protected] (M.C.); [email protected] (V.M.F.) Simple Summary: The Ephrin receptors and their ligands play important roles in organ formation and tissue repair, by orchestrating complex programs of cell adhesion and repulsion, however, this same system plays a role in cancer development In fact, EphA2 levels are higher in tumors vs normal tissue and further increased upon treatment, in vivo and in vitro. Changes in the molecular status of EphA2, of its subcellular localization, the absence of ligand and signals derived from the tumor context unleash the oncogenic role of EphA2 and its broad ability to promote resistance to radiotherapy, chemotherapy and targeted agents, including inhibitors of Epidermal-Growth-Factor- Receptor (EGFR). High levels of EphA2 may reduce response to cetuximab even in RAS wt CRC patients. In this work, we aim to review the current knowledge of the EphA2 function which is crucial for achieving a more effective therapeutic management of tumors resistant to EGFR inhibitors and to many other agents. Abstract: The Eph receptors represent the largest group among Receptor Tyrosine kinase (RTK) Citation: Cioce, M.; Fazio, V.M. -
SUPPLEMENTARY APPENDIX Exome Sequencing Reveals Heterogeneous Clonal Dynamics in Donor Cell Myeloid Neoplasms After Stem Cell Transplantation
SUPPLEMENTARY APPENDIX Exome sequencing reveals heterogeneous clonal dynamics in donor cell myeloid neoplasms after stem cell transplantation Julia Suárez-González, 1,2 Juan Carlos Triviño, 3 Guiomar Bautista, 4 José Antonio García-Marco, 4 Ángela Figuera, 5 Antonio Balas, 6 José Luis Vicario, 6 Francisco José Ortuño, 7 Raúl Teruel, 7 José María Álamo, 8 Diego Carbonell, 2,9 Cristina Andrés-Zayas, 1,2 Nieves Dorado, 2,9 Gabriela Rodríguez-Macías, 9 Mi Kwon, 2,9 José Luis Díez-Martín, 2,9,10 Carolina Martínez-Laperche 2,9* and Ismael Buño 1,2,9,11* on behalf of the Spanish Group for Hematopoietic Transplantation (GETH) 1Genomics Unit, Gregorio Marañón General University Hospital, Gregorio Marañón Health Research Institute (IiSGM), Madrid; 2Gregorio Marañón Health Research Institute (IiSGM), Madrid; 3Sistemas Genómicos, Valencia; 4Department of Hematology, Puerta de Hierro General University Hospital, Madrid; 5Department of Hematology, La Princesa University Hospital, Madrid; 6Department of Histocompatibility, Madrid Blood Centre, Madrid; 7Department of Hematology and Medical Oncology Unit, IMIB-Arrixaca, Morales Meseguer General University Hospital, Murcia; 8Centro Inmunológico de Alicante - CIALAB, Alicante; 9Department of Hematology, Gregorio Marañón General University Hospital, Madrid; 10 Department of Medicine, School of Medicine, Com - plutense University of Madrid, Madrid and 11 Department of Cell Biology, School of Medicine, Complutense University of Madrid, Madrid, Spain *CM-L and IB contributed equally as co-senior authors. Correspondence: -
Harnessing the Power of Eph/Ephrin Biosemiotics for Theranostic Applications
pharmaceuticals Review Harnessing the Power of Eph/ephrin Biosemiotics for Theranostic Applications Robert M. Hughes 1 and Jitka A.I. Virag 2,* 1 Department of Chemistry, East Carolina University, Science and Technology Building, SZ564, East 5th St, Greenville, NC 27858, USA; [email protected] 2 Department of Physiology, Brody School of Medicine, East Carolina University, Warren Life Sciences Building, LSB239, 600 Moye Blvd, Greenville, NC 27834, USA * Correspondence: [email protected] Received: 11 April 2020; Accepted: 27 May 2020; Published: 1 June 2020 Abstract: Comprehensive basic biological knowledge of the Eph/ephrin system in the physiologic setting is needed to facilitate an understanding of its role and the effects of pathological processes on its activity, thereby paving the way for development of prospective therapeutic targets. To this end, this review briefly addresses what is currently known and being investigated in order to highlight the gaps and possible avenues for further investigation to capitalize on their diverse potential. Keywords: Eph/ephrin; receptor tyrosine kinase; therapeutic target; smart drug; nanoparticles; liposomes; exosomes 1. Introduction Detection, transduction and appropriate response behavior of neighboring cells are essential components of optimal communication and the coordinated and integrated function necessary for survival. In a complex system, this is determined by the summative and timely intracellular processing of a myriad of intersecting signals from various distances and directions. The Eph receptors and ephrin ligands are the largest tyrosine kinase (RTK) superfamily, comprised of 22 known members, subdivided into A- and B-subclasses, and are heterogeneously expressed in almost every tissue [1]. These membrane-anchored proteins exhibit unique cell-to-cell communication via bidirectional signaling, which modulates cytoskeletal dynamics and thus cell–cell recognition and motility, making them integral mediators in developmental processes and the maintenance of homeostasis [2,3]. -
The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer Victoria M
Published OnlineFirst February 1, 2016; DOI: 10.1158/0008-5472.CAN-15-0847 Cancer Molecular and Cellular Pathobiology Research The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer Victoria M. Youngblood1, Laura C. Kim1, Deanna N. Edwards2, Yoonha Hwang2,3, Pranav R. Santapuram1, Steven M. Stirdivant4, Pengcheng Lu5, Fei Ye5, Dana M. Brantley-Sieders2,6, and Jin Chen1,2,3,6,7 Abstract Dysregulation of receptor tyrosine kinases (RTK) contributes to bolic pathway that generates intermediates for lipogenesis. Phar- cellular transformation and cancer progression by disrupting key macologic inhibition of glutaminase activity reduced tumor metabolic signaling pathways. The EPHA2 RTK is overexpressed growth in both ephrin-A1–depleted and EPHA2-overexpressing þ in aggressive forms of breast cancer, including the HER2 subtype, tumor allografts in vivo. Mechanistically, we show that the and correlates with poor prognosis. However, the role of EPHA2 enhanced proliferation and glutaminolysis in the absence of in tumor metabolism remains unexplored. In this study, we used ephrin-A1 were attributed to increased RhoA-dependent gluta- in vivo and in vitro models of HER2-overexpressing breast cancer to minase activity. EPHA2 depletion or pharmacologic inhibition investigate the mechanisms by which EPHA2 ligand–indepen- of Rho, glutaminase, or fatty acid synthase abrogated the dent signaling promotes tumorigenesis in the absence of its increased lipid content and proliferative effects of ephrin-A1 prototypic ligand, ephrin-A1. We demonstrate that ephrin-A1 knockdown. Together, these findings highlight a novel, unsus- loss leads to upregulated glutamine metabolism and lipid accu- pected connection between the EPHA2/ephrin-A1 signaling axis mulation that enhanced tumor growth. -
Eph Receptors and Ephrin Ligands: Embryogenesis to Tumorigenesis
Oncogene (2000) 19, 5614 ± 5619 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Eph receptors and ephrin ligands: embryogenesis to tumorigenesis Vincent C Dodelet1 and Elena B Pasquale*,1 1The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California, CA 92037, USA Protein tyrosine kinase genes are the largest family of The Eph receptors become phosphorylated at speci®c oncogenes. This is not surprising since tyrosine kinases tyrosine residues in the cytoplasmic domain following are important components of signal transduction path- ligand binding (Figure 1). Phosphorylated motifs serve ways that control cell shape, proliferation, dierentia- as sites of interaction with certain cytoplasmic signaling tion, and migration. At 14 distinct members, the Eph proteins such as non-receptor tyrosine kinases of the kinases constitute the largest family of receptor tyrosine Src and Abl families and the non-receptor phosphotyr- kinases. Although they have been most intensively osine phosphatase LMW ± PTP (low molecular weight studied for their roles in embryonic development, phosphotyrosine phosphatase); the enzymes phospholi- increasing evidence also implicates Eph family proteins pase C g, phosphatidylinositol 3-kinase, and Ras in cancer. This review will address the recent progress in GTPase activating protein; the adaptors SLAP, Grb2, understanding the function of Eph receptors in normal Grb10, and Nck; and SHEP1, a R-Ras- and Rap-1A- development and how disregulation of these functions binding protein (reviewed by Bruckner and Klein, 1998; could promote tumorigenesis. Oncogene (2000) 19, Dodelet et al., 1999; Flanagan and Vanderhaeghen, 5614 ± 5619. 1998; Kalo and Pasquale, 1999).