DOCSLIB.ORG

The Proto-Oncogene C-Kit Inhibits Tumor Growth by Behaving As a Dependence Receptor Hong Wang

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Proto-Oncogene C-Kit Inhibits Tumor Growth by Behaving As a Dependence Receptor Hong Wang The proto-oncogene c-Kit inhibits tumor growth by behaving as a dependence receptor Hong Wang To cite this version: Hong Wang. The proto-oncogene c-Kit inhibits tumor growth by behaving as a dependence receptor. Molecular biology. Université de Lyon, 2018. English. NNT : 2018LYSE1172. tel-01940383 HAL Id: tel-01940383 https://tel.archives-ouvertes.fr/tel-01940383 Submitted on 30 Nov 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Ȼ No d'ordre NNT : 2018LYSE1172 THÈSE DE DOCTORAT DE L’UNIVERSITÉ DE LYON opérée au sein de L’Université Claude Bernard Lyon 1 École Doctorale ED340 Biologie Moléculaire Intégrative et Cellulaire Spécialité de doctorat : Biologie Moléculaire et Cellulaire Soutenue publiquement le 16/10/2018, par : Hong WANG The proto-oncogene c-Kit inhibits tumor growth by behaving as a dependence receptor Devant le jury composé de : Professeur des Universités - Université Lyon 1 BLAY Jean-Yves Président Praticien Hospitalier UMR 5286 - CRCL Université de Montpellier HIBNER Urszula Directrice de Recherche Rapporteur UMR 5535 - IGMM Université Lille 1 TULASNE David Directeur de Recherche Rapporteur UMR 8161 Université de Montpellier ROCHE Serge Directeur de Recherche Examinateur UMR 5237 - CRBM Université Toulouse 3 GUILLERMET Julie Chargée de Recherche Examinatrice UMR 1037 - CRCT Université Lyon 1 MEHLEN Patrick Directeur de Recherche Examinateur UMR 5286 - CRCL Université Lyon 1 Directrice de BERNET Agnès Professeure des Universités UMR 5286 - CRCL thèse 2 UNIVERSITE CLAUDE BERNARD - LYON 1 Président de l’Université M. le Professeur Frédéric FLEURY Président du Conseil Académique M. le Professeur Hamda BEN HADID Vice-président du Conseil d’Administration M. le Professeur Didier REVEL Vice-président du Conseil Formation et Vie Universitaire M. le Professeur Philippe CHEVALIER Vice-président de la Commission Recherche M. Fabrice VALLÉE Directeur Général des Services M. Alain HELLEU COMPOSANTES SANTE Faculté de Médecine Lyon Est Claude Bernard Directeur : M. le Professeur J. ETIENNE Faculté de Médecine et de Maïeutique Lyon Sud Charles Mérieux Directeur : Mme la Professeure C. BURILLON Faculté d’Odontologie Directeur : M. le Professeur D. BOURGEOIS Institut des Sciences Pharmaceutiques et Biologiques Directeur : Mme la Professeure C. VINCIGUERRA Institut des Sciences et Techniques de la Réadaptation Directeur : M. X. PERROT Département de formation et Centre de Recherche en Biologie Humaine Directeur : Mme la Professeure A-M. SCHOTT COMPOSANTES ET DEPARTEMENTS DE SCIENCES ET TECHNOLOGIE Faculté des Sciences et Technologies Directeur : M. F. DE MARCHI Département Biologie Directeur : M. le Professeur F. THEVENARD Département Chimie Biochimie Directeur : Mme C. FELIX Département GEP Directeur : M. Hassan HAMMOURI Département Informatique Directeur : M. le Professeur S. AKKOUCHE Département Mathématiques Directeur : M. le Professeur G. TOMANOV Département Mécanique Directeur : M. le Professeur H. BEN HADID Département Physique Directeur : M. B. GUIDERDONI UFR Sciences et Techniques des Activités Physiques et Sportives Directeur : M.Y. VANPOULLE Observatoire des Sciences de l’Univers de Lyon Directeur : M. le Professeur J-C PLENET Polytech Lyon Directeur : M. le Professeur E. PERRIN Ecole Supérieure de Chimie Physique Electronique Directeur : M. G. PIGNAULT Institut Universitaire de Technologie de Lyon 1 Directeur : M. le Professeur C. VITON Ecole Supérieure du Professorat et de l’Education Directeur : M. le Professeur A. MOUGNIOTTE Institut de Science Financière et d’Assurances Directeur : M. N. LEBOISNE 3 4 ABSTRACT c-Kit has been generally considered as a receptor tyrosine kinase and a proto- oncogene, whose upregulation and mutation lead to tumor progression through its kinase activity. Clinically, drugs targeting the kinase activity of c-Kit, such as Imatinib (Gleevec), have been wildly used to treat patients with c-Kit related diseases. While the role of c-Kit as a proto-oncogene is of no doubt, some research reports and database analysis do not fit well the tumor promoting role of c-Kit, indicating a possible different role of c-Kit in cancer. Here, we show that c-Kit belongs to the dependence receptor family, similarly to other receptor tyrosine kinases such as MET, RET and TrkC. In the absent of its ligand SCF (stem cell factor), instead of staying inactive, c-Kit triggers apoptosis, which can be enhanced by silencing its kinase activity. Besides, we have shown that c-Kit is able to bind and activate caspase-9. Moreover, similarly to other dependence receptors, c-Kit is also cleaved by caspases-like protease at aspartic acid residue D816, which is crucial for its pro-apoptotic activity. The mutation of D816 site inhibits the c-Kit/caspase-9 binding and silences the pro-apoptotic activity of c-Kit. Of interest, c-Kit D816 mutation is one of the most common mutation of this receptor in many c-Kit related cancers and it promotes resistance against Gleevec treatment. We also show that overexpression of kinase mutated c-Kit is able to inhibit tumor growth in animal models, while the mutation of D816 site impairs the tumor suppressing activity. Furthermore, we develop a tool to block the SCF/c-Kit interaction, which unleashes the pro-apoptotic activity of c-Kit in cancers expressing this receptor. By using the pro-apoptotic activity of c-Kit, in combination with kinase inhibitors like Gleevec, we propose a novel therapeutic strategy. In conclusion, we demonstrate that c-Kit is a member of dependence receptor family, harboring intrinsic pro- apoptotic activity, which can be used as an alternative tool in cancer treatment. 5 RESUME c-Kit est généralement considéré comme un récepteur à tyrosine kinase et comme un proto-oncogène, dont la surexpression et la mutation conduisent à une progression tumorale médiée par son activité kinase. En clinique, les traitements ciblant l’activité kinase de c-Kit, comme l’Imatinib (Gleevec), ont été largement utilisés pour traiter les patients atteints de maladies liées à c-Kit. Alors que le rôle de c-Kit comme proto- oncogène ne fait aucun doute, certaines études et analyses de bases de données diffèrent avec l’idée d’un rôle pro-tumoral de c-Kit, laissant penser à un rôle différent de c-Kit dans le cancer. Ici, nous montrons que c-Kit appartient à la famille des récepteurs à dépendance, de la même façon que d’autres récepteurs de la famille des tyrosine kinases tel que MET, RET et TrkC. En absence de son ligand Stem Cell Factor (SCF), au lieu de rester inactif, c-Kit déclenche l’apoptose, qui peut être renforcée par l’invalidation de son activité kinase. En parallèle, nous montrons que c-Kit est capable de se lier à la caspase- 9 et de l’activer. De plus, à la manière d’autres récepteurs à dépendance, c-Kit est aussi clivé par des protéases de type caspase sur son résidu acide aspartique D816, qui est nécessaire à son activité pro-apoptotique. La mutation du site D816 inhibe l’interaction entre c-kit et la caspase-9 et invalide l’activité pro-apoptotique de c-Kit. De façon intéressante, la mutation D816 est l’une des mutations les plus communes de ce récepteur dans la plupart des cancers liés à c-Kit, et cette mutation favorise la résistance au traitement Gleevec. Nous montrons aussi que la surexpression de c-Kit invalidé pour son activité kinase est capable d’inhiber la croissance tumorale dans des modèles animaux, alors que la mutation du site D816 empêche son effet suppresseur de tumeur. En outre, nous avons développé un outil permettant de bloquer l’interaction entre SCF et c-Kit, déclenchant l’activité pro-apoptotique de c-Kit dans les cancers positifs pour ce récepteur. En utilisant l’activité pro-apoptotique de c-Kit, en combinaison avec des inhibiteurs de kinases comme le Gleevec, nous proposons une nouvelle stratégie thérapeutique. En conclusion, nous démontrons que c-Kit est un membre de la famille des récepteurs à dépendance, présentant une activité pro-apoptotique, et pouvant être utilisé comme un outil alternatif dans le cadre d’un traitement contre le cancer. 6 Table of Contents ACKNOWLEDGEMENTS ................................................................................................................... 9 I. Introduction ................................................................................................................................ 11 1. Apoptosis and Dependence Receptor ................................................................................... 12 1.1 Cell death ......................................................................................................................... 12 1.2 Apoptosis ......................................................................................................................... 12 1.3 The dependence receptor family .................................................................................... 23 1.4 Dependence receptors are caspase substrates ............................................................... 26 1.5 Mechanism of dependence receptors pro-apoptotic activity ........................................
Load more

Recommended publications
  • Gene Symbol Gene Description ACVR1B Activin a Receptor, Type IB
    Table S1. Kinase clones included in human kinase cDNA library for yeast two-hybrid screening Gene Symbol Gene Description ACVR1B activin A receptor, type IB ADCK2 aarF domain containing kinase 2 ADCK4 aarF domain containing kinase 4 AGK multiple substrate lipid kinase;MULK AK1 adenylate kinase 1 AK3 adenylate kinase 3 like 1 AK3L1 adenylate kinase 3 ALDH18A1 aldehyde dehydrogenase 18 family, member A1;ALDH18A1 ALK anaplastic lymphoma kinase (Ki-1) ALPK1 alpha-kinase 1 ALPK2 alpha-kinase 2 AMHR2 anti-Mullerian hormone receptor, type II ARAF v-raf murine sarcoma 3611 viral oncogene homolog 1 ARSG arylsulfatase G;ARSG AURKB aurora kinase B AURKC aurora kinase C BCKDK branched chain alpha-ketoacid dehydrogenase kinase BMPR1A bone morphogenetic protein receptor, type IA BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) BRAF v-raf murine sarcoma viral oncogene homolog B1 BRD3 bromodomain containing 3 BRD4 bromodomain containing 4 BTK Bruton agammaglobulinemia tyrosine kinase BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) C9orf98 chromosome 9 open reading frame 98;C9orf98 CABC1 chaperone, ABC1 activity of bc1 complex like (S. pombe) CALM1 calmodulin 1 (phosphorylase kinase, delta) CALM2 calmodulin 2 (phosphorylase kinase, delta) CALM3 calmodulin 3 (phosphorylase kinase, delta) CAMK1 calcium/calmodulin-dependent protein kinase I CAMK2A calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha CAMK2B calcium/calmodulin-dependent
    [Show full text]
  • Overexpresssion of Tyrosine Kinase Discoidin Domain Receptor I (DDR1 ) in Transitional Cell Carcinoma
    Overexpresssion of Tyrosine Kinase Discoidin domain receptor I (DDR1 ) in Transitional cell Carcinoma Szu-Ting Chen,* and Shie-Liang Hsieh* Institute and Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; To whom proofs are to be sent: Shie-Liang Hsieh, Department and Institute of Microbiology and Immunology, National Yang-Ming University, Shih-Pai, Taipei 112, Taiwan. E-mail address: [email protected] Telephone number: 886-2-28267161 Fax number: 886-2-28277933 INTRODUCTION DDR1, discoidin domain receptor 1, belongs to the novel subfamily of tyrosine kinase receptor, which forms homodimer upon ligand engagement. DDR1 is distinguished from other receptor tyrosine kinase by the discoidin domain in their extracellular domain, which is a homology region originally identified in Dictyostelium discoideum (slime mold) protein, discoidin I, and involves in cells aggregation. Discoidin-1 has binding specificity toward galactose and N-acetyl galactosamine and is essential for slime mold cells adhesion, migration and aggregation during its development, suggesting that DDR1 shared similar biologically function in mammalian [1-3]. DDR1 has been found mainly distributed and in human tissue epithelia, such as kidney, breast, lung [3], bronchial [4] and keratinocytes [5]. Furthermore, DDR1 has been also reported its expression in immune system like the monocyte-derived dendritic cells, annotated as CD167 [6] and macrophage[7]. However, recently, the overexpression of DDR1 has been detected in several human cancers, such as primary breast cancer [1, 8, 9] ovarian[10, 11], brain[12], esophageal cancer [13], and TCC (our data unpublished) in which raising the possibility that DDR1 may play a important role in tumorigenesis [14].
    [Show full text]
  • PD-L1 Expression and Clinical Outcomes to Cabozantinib
    Author Manuscript Published OnlineFirst on August 1, 2019; DOI: 10.1158/1078-0432.CCR-19-1135 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. PD-L1 expression and clinical outcomes to cabozantinib, everolimus and sunitinib in patients with metastatic renal cell carcinoma: analysis of the randomized clinical trials METEOR and CABOSUN Abdallah Flaifel1, Wanling Xie2, David A. Braun3, Miriam Ficial1, Ziad Bakouny3, Amin H. Nassar3, Rebecca B. Jennings1, Bernard Escudier4, Daniel J. George5, Robert J. Motzer6, Michael J. Morris6, Thomas Powles7, Evelyn Wang8, Ying Huang9, Gordon J. Freeman3, Toni K. Choueiri*3, Sabina Signoretti*1,9 1Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2Department of Data Sciences, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 3Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 4Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France 5Department Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA 6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA 7Department of Experimental Cancer Medicine, Barts Cancer Institute, London, UK 8Exelixis Inc., South San Francisco, CA, USA 9Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA *equal contribution Correspondence: Toni K. Choueiri, M.D., Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 1230, 450 Brookline Ave, Boston, MA 02115; Phone: 617-632-5456; Fax: 617-632-2165 E-mail: [email protected] Or Sabina Signoretti, M.D., Department of Pathology, Brigham and Women's Hospital, Thorn Building 504A, 75 Francis Street, Boston, MA 02115; Phone: 617-525-7437; Fax: 617-264-5169 Email: [email protected] Downloaded from clincancerres.aacrjournals.org on September 29, 2021.
    [Show full text]
  • Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse
    Welcome to More Choice CD Marker Handbook For more information, please visit: Human bdbiosciences.com/eu/go/humancdmarkers Mouse bdbiosciences.com/eu/go/mousecdmarkers Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse CD3 CD3 CD (cluster of differentiation) molecules are cell surface markers T Cell CD4 CD4 useful for the identification and characterization of leukocytes. The CD CD8 CD8 nomenclature was developed and is maintained through the HLDA (Human Leukocyte Differentiation Antigens) workshop started in 1982. CD45R/B220 CD19 CD19 The goal is to provide standardization of monoclonal antibodies to B Cell CD20 CD22 (B cell activation marker) human antigens across laboratories. To characterize or “workshop” the antibodies, multiple laboratories carry out blind analyses of antibodies. These results independently validate antibody specificity. CD11c CD11c Dendritic Cell CD123 CD123 While the CD nomenclature has been developed for use with human antigens, it is applied to corresponding mouse antigens as well as antigens from other species. However, the mouse and other species NK Cell CD56 CD335 (NKp46) antibodies are not tested by HLDA. Human CD markers were reviewed by the HLDA. New CD markers Stem Cell/ CD34 CD34 were established at the HLDA9 meeting held in Barcelona in 2010. For Precursor hematopoetic stem cell only hematopoetic stem cell only additional information and CD markers please visit www.hcdm.org. Macrophage/ CD14 CD11b/ Mac-1 Monocyte CD33 Ly-71 (F4/80) CD66b Granulocyte CD66b Gr-1/Ly6G Ly6C CD41 CD41 CD61 (Integrin b3) CD61 Platelet CD9 CD62 CD62P (activated platelets) CD235a CD235a Erythrocyte Ter-119 CD146 MECA-32 CD106 CD146 Endothelial Cell CD31 CD62E (activated endothelial cells) Epithelial Cell CD236 CD326 (EPCAM1) For Research Use Only.
    [Show full text]
  • Sonic Hedgehog-Gli1 Signaling and Cellular Retinoic Acid Binding Protein 1 Gene Regulation in Motor Neuron Differentiation and Diseases
    International Journal of Molecular Sciences Article Sonic Hedgehog-Gli1 Signaling and Cellular Retinoic Acid Binding Protein 1 Gene Regulation in Motor Neuron Differentiation and Diseases Yu-Lung Lin y, Yi-Wei Lin y, Jennifer Nhieu y, Xiaoyin Zhang and Li-Na Wei * Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] (Y.-L.L.); [email protected] (Y.-W.L.); [email protected] (J.N.); [email protected] (X.Z.) * Correspondence: [email protected]; Tel.: +1-612-6259402 Contributed equally. y Received: 29 April 2020; Accepted: 7 June 2020; Published: 9 June 2020 Abstract: Cellular retinoic acid-binding protein 1 (CRABP1) is highly expressed in motor neurons. Degenerated motor neuron-like MN1 cells are engineered by introducing SODG93A or AR-65Q to model degenerated amyotrophic lateral sclerosis (ALS) or spinal bulbar muscular atrophy neurons. Retinoic acid (RA)/sonic hedgehog (Shh)-induced embryonic stem cells differentiation into motor neurons are employed to study up-regulation of Crabp1 by Shh. In SODG93A or AR-65Q MN1 neurons, CRABP1 level is reduced, revealing a correlation of motor neuron degeneration with Crabp1 down-regulation. Up-regulation of Crabp1 by Shh is mediated by glioma-associated oncogene homolog 1 (Gli1) that binds the Gli target sequence in Crabp10s neuron-specific regulatory region upstream of minimal promoter. Gli1 binding triggers chromatin juxtaposition with minimal promoter, activating transcription. Motor neuron differentiation and Crabp1 up-regulation are both inhibited by blunting Shh with Gli inhibitor GANT61. Expression data mining of ALS and spinal muscular atrophy (SMA) motor neurons shows reduced CRABP1, coincided with reduction in Shh-Gli1 signaling components.
    [Show full text]
  • Role of Gas1 Down-Regulation in Mitogenic Stimulation of Quiescent NIH3T3 Cells by V-Src
    Oncogene (1998) 17, 1629 ± 1638 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Role of Gas1 down-regulation in mitogenic stimulation of quiescent NIH3T3 cells by v-Src Milena Grossi1, S Anna La Rocca1, Gloria Pierluigi1, Serena Vannucchi1, Elisabetta M Ruaro2, Claudio Schneider2 and Franco TatoÁ 1 1Istituto Pasteur-Fondazione Cenci-Bolognetti, Dipartimento di Biologia Cellulare e dello Sviluppo, UniversitaÁ di Roma `La Sapienza', Vie degli Apuli, 100185-Roma, Italy and 2Laboratorio Nazionale Consorzio Interuniversitario per le Biotecnologie, 34012-Trieste, Italy Quiescent mammalian ®broblasts can be induced to re- interfering with the early serum response (Del Sal et enter the cell cycle by growth factors and oncoproteins. al., 1992). Gas1-induced growth arrest appears to be We studied the pathway(s) through which v-Src, the mediated by p53, with no requirement for its sequence- oncogenic tyrosine kinase encoded by the v-src oncogene speci®c transactivating function (Del Sal et al., 1995). of Rous sarcoma virus, forces serum-starved NIH3T3 Ample evidence documents that positive signalling cells to enter S-phase. To this purpose, we isolated and from growth factors and oncogene products very often characterized a polyclonal population of NIH3T3 cells involves the activation of a major biochemical pathway transformed by the MR31 retroviral vector, encoding known as the Ras-pathway (Kazlauskas, 1994; Mar- G418 resistance and the v-src temperature-sensitive allele shall, 1994; McCormick, 1994; Schlessinger, 1994). In from the mutant ts LA31 PR-A. NIH(MR31) cells order to activate this pathway, ultimately leading to S- displayed a temperature-conditional transformed pheno- phase entry, transduction of signals generated at the type and could be made quiescent by serum deprivation cell membrane is needed and performed by adaptor at the restrictive temperature.
    [Show full text]
  • Patents Related to EPH Receptors and Ligands
    NEWS & ANALYSIS discuss EPH receptor–ephrin signalling Patents related to EPH receptors and its role in disorders such as tumour and ligands growth and progression, nerve injury and inflammation, and highlight therapeutic EPH receptors are a family of receptor approaches that are currently under tyrosine kinases that, together with their investigation. Here in TABLE 1 we highlight ligands, are involved in cell positioning, patent applications published in the past tissue and organ patterning as well as the 3 years related to EPH receptors and ligands. control of cell survival. In their Review Data were researched using the Espacenet on page 39, Lackman and colleagues database. Table 1 | Recent patent applications related to EPH receptors and ligands Nature Reviews | Drug Discovery Publication Applicants Subject numbers NZ 581397 AstraZeneca Pyrimidine compounds that inhibit EPH receptors and are useful for treating cancer HK 1108702 Sanford-Burnham Peptides that selectively bind to EPH type-B receptors (EPHBs); useful for tumour imaging and the Institute treatment of neoplastic disease, neurological disease and vascular disease US 2013091591 California Institute of During angiogenesis, arterial cells express ephrin B2, and its receptor EPHB4 is expressed on venous Technology cells; this distinction can be used in methods to alter angiogenesis and to assess the effect of drugs WO 2013052710 Expression Pathology Selected reaction monitoring mass spectrometry-based and multiple reaction monitoring mass spectrometry-based assays for quantifying
    [Show full text]
  • Human FLT4 / VEGFR3 ELISA Kit (ARG82047)
    Product datasheet [email protected] ARG82047 Package: 96 wells Human FLT4 / VEGFR3 ELISA Kit Store at: 4°C Summary Product Description Human FLT4 / VEGFR3 ELISA Kit is an Enzyme Immunoassay kit for the quantification of Human FLT4 / VEGFR3 in serum, plasma and cell culture supernatants. Tested Reactivity Hu Tested Application ELISA Target Name FLT4 / VEGFR3 Conjugation HRP Conjugation Note Substrate: TMB and read at 450 nm. Sensitivity 78 pg/ml Sample Type Serum, plasma and cell culture supernatants. Standard Range 156 - 10000 pg/ml Sample Volume 100 µl Alternate Names FLT-4; FLT41; Vascular endothelial growth factor receptor 3; VEGFR3; VEGFR-3; PCL; Tyrosine-protein kinase receptor FLT4; LMPH1A; EC 2.7.10.1; Fms-like tyrosine kinase 4 Application Instructions Assay Time 4.5 hours Properties Form 96 well Storage instruction Store the kit at 2-8°C. Keep microplate wells sealed in a dry bag with desiccants. Do not expose test reagents to heat, sun or strong light during storage and usage. Please refer to the product user manual for detail temperatures of the components. Note For laboratory research only, not for drug, diagnostic or other use. Bioinformation Gene Symbol FLT4 Gene Full Name fms-related tyrosine kinase 4 Background This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA. [provided by RefSeq, Jul 2008] Function Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development.
    [Show full text]
  • Ephb3 Suppresses Non-Small-Cell Lung Cancer Metastasis Via a PP2A/RACK1/Akt Signalling Complex
    ARTICLE Received 7 Nov 2011 | Accepted 11 Jan 2012 | Published 7 Feb 2012 DOI: 10.1038/ncomms1675 EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex Guo Li1, Xiao-Dan Ji1, Hong Gao1, Jiang-Sha Zhao1, Jun-Feng Xu1, Zhi-Jian Sun1, Yue-Zhen Deng1, Shuo Shi1, Yu-Xiong Feng1, Yin-Qiu Zhu1, Tao Wang2, Jing-Jing Li1 & Dong Xie1 Eph receptors are implicated in regulating the malignant progression of cancer. Here we find that despite overexpression of EphB3 in human non-small-cell lung cancer, as reported previously, the expression of its cognate ligands, either ephrin-B1 or ephrin-B2, is significantly downregulated, leading to reduced tyrosine phosphorylation of EphB3. Forced activation of EphB3 kinase in EphB3-overexpressing non-small-cell lung cancer cells inhibits cell migratory capability in vitro as well as metastatic seeding in vivo. Furthermore, we identify a novel EphB3-binding protein, the receptor for activated C-kinase 1, which mediates the assembly of a ternary signal complex comprising protein phosphatase 2A, Akt and itself in response to EphB3 activation, leading to reduced Akt phosphorylation and subsequent inhibition of cell migration. Our study reveals a novel tumour-suppressive signalling pathway associated with kinase-activated EphB3 in non-small-cell lung cancer, and provides a potential therapeutic strategy by activating EphB3 signalling, thus inhibiting tumour metastasis. 1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of Chinese Academy of Sciences, Shanghai 200031, China. 2 The Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai 200433, China.
    [Show full text]
  • Original Article ERBB3, IGF1R, and TGFBR2 Expression Correlate With
    Am J Cancer Res 2018;8(5):792-809 www.ajcr.us /ISSN:2156-6976/ajcr0077452 Original Article ERBB3, IGF1R, and TGFBR2 expression correlate with PDGFR expression in glioblastoma and participate in PDGFR inhibitor resistance of glioblastoma cells Kang Song1,2*, Ye Yuan1,2*, Yong Lin1,2, Yan-Xia Wang1,2, Jie Zhou1,2, Qu-Jing Gai1,2, Lin Zhang1,2, Min Mao1,2, Xiao-Xue Yao1,2, Yan Qin1,2, Hui-Min Lu1,2, Xiang Zhang1,2, You-Hong Cui1,2, Xiu-Wu Bian1,2, Xia Zhang1,2, Yan Wang1,2 1Department of Pathology, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; 2Key Laboratory of Tumor Immunology and Pathology of Ministry of Education, Chongqing 400038, China. *Equal contributors. Received April 6, 2018; Accepted April 9, 2018; Epub May 1, 2018; Published May 15, 2018 Abstract: Glioma, the most prevalent malignancy in brain, is classified into four grades (I, II, III, and IV), and grade IV glioma is also known as glioblastoma multiforme (GBM). Aberrant activation of receptor tyrosine kinases (RTKs), including platelet-derived growth factor receptor (PDGFR), are frequently observed in glioma. Accumulating evi- dence suggests that PDGFR plays critical roles during glioma development and progression and is a promising drug target for GBM therapy. However, PDGFR inhibitor (PDGFRi) has failed in clinical trials, at least partially, due to the activation of other RTKs, which compensates for PDGFR inhibition and renders tumor cells resistance to PDGFRi. Therefore, identifying the RTKs responsible for PDGFRi resistance might provide new therapeutic targets to syner- getically enhance the efficacy of PDGFRi.
    [Show full text]
  • Management of Brain and Leptomeningeal Metastases from Breast Cancer
    International Journal of Molecular Sciences Review Management of Brain and Leptomeningeal Metastases from Breast Cancer Alessia Pellerino 1,* , Valeria Internò 2 , Francesca Mo 1, Federica Franchino 1, Riccardo Soffietti 1 and Roberta Rudà 1,3 1 Department of Neuro-Oncology, University and City of Health and Science Hospital, 10126 Turin, Italy; [email protected] (F.M.); [email protected] (F.F.); riccardo.soffi[email protected] (R.S.); [email protected] (R.R.) 2 Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; [email protected] 3 Department of Neurology, Castelfranco Veneto and Treviso Hospital, 31100 Treviso, Italy * Correspondence: [email protected]; Tel.: +39-011-6334904 Received: 11 September 2020; Accepted: 10 November 2020; Published: 12 November 2020 Abstract: The management of breast cancer (BC) has rapidly evolved in the last 20 years. The improvement of systemic therapy allows a remarkable control of extracranial disease. However, brain (BM) and leptomeningeal metastases (LM) are frequent complications of advanced BC and represent a challenging issue for clinicians. Some prognostic scales designed for metastatic BC have been employed to select fit patients for adequate therapy and enrollment in clinical trials. Different systemic drugs, such as targeted therapies with either monoclonal antibodies or small tyrosine kinase molecules, or modified chemotherapeutic agents are under investigation. Major aims are to improve the penetration of active drugs through the blood–brain barrier (BBB) or brain–tumor barrier (BTB), and establish the best sequence and timing of radiotherapy and systemic therapy to avoid neurocognitive impairment. Moreover, pharmacologic prevention is a new concept driven by the efficacy of targeted agents on macrometastases from specific molecular subgroups.
    [Show full text]
  • Neurotrophin-3 Production Promotes Human Neuroblastoma Cell Survival by Inhibiting Trkc-Induced Apoptosis
    Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis Jimena Bouzas-Rodriguez, … , Servane Tauszig-Delamasure, Patrick Mehlen J Clin Invest. 2010;120(3):850-858. https://doi.org/10.1172/JCI41013. Research Article Oncology Tropomyosin-related kinase receptor C (TrkC) is a neurotrophin receptor with tyrosine kinase activity that was expected to be oncogenic. However, it has several characteristics of a tumor suppressor: its expression in tumors has often been associated with good prognosis; and it was recently demonstrated to be a dependence receptor, transducing different positive signals in the presence of ligand but inducing apoptosis in the absence of ligand. Here we show that the TrkC ligand neurotrophin-3 (NT-3) is upregulated in a large fraction of aggressive human neuroblastomas (NBs) and that it blocks TrkC-induced apoptosis of human NB cell lines, consistent with the idea that TrkC is a dependence receptor. Functionally, both siRNA knockdown of NT-3 expression and incubation with a TrkC-specific blocking antibody triggered apoptosis in human NB cell lines. Importantly, disruption of the NT-3 autocrine loop in malignant human neuroblasts triggered in vitro NB cell death and inhibited tumor growth and metastasis in both a chick and a mouse xenograft model. Thus, we believe that our data suggest that NT-3/TrkC disruption is a putative alternative targeted therapeutic strategy for the treatment of NB. Find the latest version: https://jci.me/41013/pdf Research article Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis Jimena Bouzas-Rodriguez,1 Jorge Ruben Cabrera,1 Céline Delloye-Bourgeois,1 Gabriel Ichim,1 Jean-Guy Delcros,1 Marie-Anne Raquin,2 Raphaël Rousseau,3 Valérie Combaret,3 Jean Bénard,4 Servane Tauszig-Delamasure,1 and Patrick Mehlen1 1Apoptosis, Cancer and Development Laboratory–Equipe labellisée “La Ligue,” CNRS UMR5238, Université de Lyon, France.
    [Show full text]