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Abnormal Embryonic Lymphatic Vessel Development in Tie1 Hypomorphic Mice Xianghu Qu, Kevin Tompkins, Lorene E
© 2014. Published by The Company of Biologists Ltd | Development (2014) 141, 1417 doi:10.1242/dev.108969 CORRECTION Abnormal embryonic lymphatic vessel development in Tie1 hypomorphic mice Xianghu Qu, Kevin Tompkins, Lorene E. Batts, Mira Puri and H. Scott Baldwin There was an error published in Development 137, 1285-1295. Author name H. Scott Baldwin was incomplete. The correct author list appears above. The authors apologise to readers for this mistake. 1417 RESEARCH ARTICLE 1285 Development 137, 1285-1295 (2010) doi:10.1242/dev.043380 © 2010. Published by The Company of Biologists Ltd Abnormal embryonic lymphatic vessel development in Tie1 hypomorphic mice Xianghu Qu1, Kevin Tompkins1, Lorene E. Batts1, Mira Puri2 and Scott Baldwin1,3,* SUMMARY Tie1 is an endothelial receptor tyrosine kinase that is essential for development and maintenance of the vascular system; however, the role of Tie1 in development of the lymphatic vasculature is unknown. To address this question, we first documented that Tie1 is expressed at the earliest stages of lymphangiogenesis in Prox1-positive venous lymphatic endothelial cell (LEC) progenitors. LEC Tie1 expression is maintained throughout embryonic development and persists in postnatal mice. We then generated two lines of Tie1 mutant mice: a hypomorphic allele, which has reduced expression of Tie1, and a conditional allele. Reduction of Tie1 levels resulted in abnormal lymphatic patterning and in dilated and disorganized lymphatic vessels in all tissues examined and in impaired lymphatic drainage in embryonic skin. Homozygous hypomorphic mice also exhibited abnormally dilated jugular lymphatic vessels due to increased production of Prox1-positive LECs during initial lymphangiogenesis, indicating that Tie1 is required for the early stages of normal lymphangiogenesis. -
Discovery of Orphan Receptor Tie1 and Angiopoietin Ligands Ang1 and Ang4 As Novel GAG-Binding Partners
78 Chapter 3 Discovery of Orphan Receptor Tie1 and Angiopoietin Ligands Ang1 and Ang4 as Novel GAG-Binding Partners 79 3.1 Abstract The Tie/Ang signaling axis is necessary for proper vascular development and remodeling. However, the mechanisms that modulate signaling through this receptor tyrosine kinase pathway are relatively unclear. In particular, the role of the orphan receptor Tie1 is highly disputed. Although this protein is required for survival, Tie1 has been found both to inhibit and yet be necessary for Tie2 signaling. While differing expression levels have been put forth as an explanation for its context-specific activity, the lack of known endogenous ligands for Tie1 has severely hampered understanding its molecular mode of action. Here we describe the discovery of orphan receptor Tie1 and angiopoietin ligands Ang1 and Ang4 as novel GAG binding partners. We localize the binding site of GAGs to the N- terminal region of Tie1, which may provide structural insights into the importance of this interaction regarding the formation of Tie1-Tie2 heterodimerization. Furthermore, we use our mutagenesis studies to guide the generation of a mouse model that specifically ablates GAG-Tie1 binding in vivo for further characterization of the functional outcomes of GAG-Tie1 binding. We also show that GAGs can form a trimeric complex with Ang1/4 and Tie2 using our microarray technology. Finally, we use our HaloTag glycan engineering platform to modify the cell surface of endothelial cells and demonstrate that HS GAGs can potentiate Tie2 signaling in a sulfation-specific manner, providing the first evidence of the involvement of HS GAGs in Tie/Ang signaling and delineating further the integral role of HS GAGs in angiogenesis. -
Src-Family Kinases Impact Prognosis and Targeted Therapy in Flt3-ITD+ Acute Myeloid Leukemia
Src-Family Kinases Impact Prognosis and Targeted Therapy in Flt3-ITD+ Acute Myeloid Leukemia Title Page by Ravi K. Patel Bachelor of Science, University of Minnesota, 2013 Submitted to the Graduate Faculty of School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2019 Commi ttee Membership Pa UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE Commi ttee Membership Page This dissertation was presented by Ravi K. Patel It was defended on May 31, 2019 and approved by Qiming (Jane) Wang, Associate Professor Pharmacology and Chemical Biology Vaughn S. Cooper, Professor of Microbiology and Molecular Genetics Adrian Lee, Professor of Pharmacology and Chemical Biology Laura Stabile, Research Associate Professor of Pharmacology and Chemical Biology Thomas E. Smithgall, Dissertation Director, Professor and Chair of Microbiology and Molecular Genetics ii Copyright © by Ravi K. Patel 2019 iii Abstract Src-Family Kinases Play an Important Role in Flt3-ITD Acute Myeloid Leukemia Prognosis and Drug Efficacy Ravi K. Patel, PhD University of Pittsburgh, 2019 Abstract Acute myelogenous leukemia (AML) is a disease characterized by undifferentiated bone-marrow progenitor cells dominating the bone marrow. Currently the five-year survival rate for AML patients is 27.4 percent. Meanwhile the standard of care for most AML patients has not changed for nearly 50 years. We now know that AML is a genetically heterogeneous disease and therefore it is unlikely that all AML patients will respond to therapy the same way. Upregulation of protein-tyrosine kinase signaling pathways is one common feature of some AML tumors, offering opportunities for targeted therapy. -
Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer Running Title
Author Manuscript Published OnlineFirst on January 20, 2017; DOI: 10.1158/0008-5472.CAN-16-1921 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Uvyr)Thvp ru v rpr hv h r hpvhrq vu rhhv v vh py rphy phpr Svt vyr) 6u ) " #$ % & '$ $( $)*# $ ,$$ - ./ 0 1 " , $'2 / ' - , $$03$, 4, 5$ $ 6 7$ % & 8 8$ 9 6ssvyvhv) . 8 : .2 $ 5 1 $ ; $ ;# < %. 8 : ., , $ ;# $ < -: . $, 8 $ . . 8 ; $ ;# /. 8 : . $; $ ;# < 0= $ 1 2 . , >2,, $ ?&, $ 2 . & $ , $@ ABA%B, $ < 4: . $ $ $ ; $ ;# < 6: .2 $ 5 1 $ .@ $ $ $ = $ ; $ ;# < Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 20, 2017; DOI: 10.1158/0008-5472.CAN-16-1921 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. & 8 * $$ < 9& $8 C 8 < 8$ D< < 8syvp s vr rC & . $@ $, $ ', $E $ . $ 8$:7'@ < % Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 20, 2017; DOI: 10.1158/0008-5472.CAN-16-1921 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 6i hpC& 8 . . $ $ >? $ <& . # $# . $ $ .464A6 22)2 . $. E<& # $ >?. $ . ). $ . ) . $$ 222 2 < $ $ . @ . <& 8$. $ ., ::)$$@,. ) $ ),@$$<F .8 222 . , $) ,::)$$ ), $E <& 8# # $8 , < - Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 20, 2017; DOI: 10.1158/0008-5472.CAN-16-1921 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. D qpv #$ .$$) $ .. 8 >&5?>?<& . 8@ #$ $#$ # $ 8$ .8 . -
Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia
cancers Review Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia Kalpana K. Bhanumathy 1,*, Amrutha Balagopal 1, Frederick S. Vizeacoumar 2 , Franco J. Vizeacoumar 1,3, Andrew Freywald 2 and Vincenzo Giambra 4,* 1 Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] (A.B.); [email protected] (F.J.V.) 2 Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] (F.S.V.); [email protected] (A.F.) 3 Cancer Research Department, Saskatchewan Cancer Agency, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada 4 Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy * Correspondence: [email protected] (K.K.B.); [email protected] (V.G.); Tel.: +1-(306)-716-7456 (K.K.B.); +39-0882-416574 (V.G.) Simple Summary: Protein phosphorylation is a key regulatory mechanism that controls a wide variety of cellular responses. This process is catalysed by the members of the protein kinase su- perfamily that are classified into two main families based on their ability to phosphorylate either tyrosine or serine and threonine residues in their substrates. Massive research efforts have been invested in dissecting the functions of tyrosine kinases, revealing their importance in the initiation and progression of human malignancies. Based on these investigations, numerous tyrosine kinase inhibitors have been included in clinical protocols and proved to be effective in targeted therapies for various haematological malignancies. -
Activation of Transmembrane Cell-Surface Receptors Via a Common Mechanism? the ‘‘Rotation Model’’
Insights & Perspectives Hypotheses Activation of transmembrane cell-surface receptors via a common mechanism? The ‘‘rotation model’’ Ichiro N. Maruyama It has long been thought that transmembrane cell-surface receptors, such as typically consist of an extracellular receptor tyrosine kinases and cytokine receptors, among others, are activated by domain (ECD) and an intracellular ligand binding through ligand-induced dimerization of the receptors. However, domain (ICD) separated by a single transmembrane domain (TMD), with there is growing evidence that prior to ligand binding, various transmembrane the exception of bacterial receptors receptors have a preformed, yet inactive, dimeric structure on the cell surface. such as the aspartate receptor (Tar) Various studies also demonstrate that during transmembrane signaling, ligand and the serine receptor (Tsr), which binding to the extracellular domain of receptor dimers induces a rotation of have another TMD at their amino transmembrane domains, followed by rearrangement and/or activation of termini. Ligand binding to their ECDs often regulates kinases that are either intracellular domains. The paper here describes transmembrane cell-surface integrated into the receptor ICD, or receptors that are known or proposed to exist in dimeric form prior toligand binding, physically associated with the ICD. and discusses how these preformed dimers are activated by ligand binding. Apart from receptors that initiate signaling pathways inside cells via Keywords: tyrosine phosphorylation, there are .cytokine; dimerization; ligand binding; preformed dimer; transmembrane receptors in bacteria, fungi, and plants signaling; tyrosine kinase that phosphorylate histidine residues upon ligand binding. Furthermore, natriuretic peptide receptors, which are receptor-type guanylyl cyclases, Introduction cell membranes to the cytoplasm, and produce cGMP upon peptide binding. -
Structural Basis of Tie2 Activation and Tie2/Tie1 Heterodimerization
Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization Veli-Matti Leppänena,1, Pipsa Saharinena,b, and Kari Alitaloa,b,1 aWihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; and bTranslational Cancer Biology Program, Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland Contributed by Kari Alitalo, March 8, 2017 (sent for review September 28, 2016; reviewed by Joseph Schlessinger and Michel O. Steinmetz) The endothelial cell (EC)-specific receptor tyrosine kinases mice lacking Tie1 develop severe edema around E13.5 because Tie1 and Tie2 are necessary for the remodeling and maturation of compromised microvessel integrity and defects in lymphatic of blood and lymphatic vessels. Angiopoietin-1 (Ang1) growth vasculature and die subsequently (15, 16). Furthermore, Tie1 has factor is a Tie2 agonist, whereas Ang2 functions as a context- critical functions in vascular pathologies, e.g., in tumor angio- dependent agonist/antagonist. The orphan receptor Tie1 modu- genesis and atherosclerosis progression (12, 17). lates Tie2 activation, which is induced by association of angio- In EC monolayers, angiopoietins stimulate Tie receptor trans- cis – trans location to cell–cell junctions for Tie2 trans-association, whereas poietins with Tie2 in and across EC EC junctions in . – Except for the binding of the C-terminal angiopoietin domains in the absence of cell cell adhesion the Tie receptors are an- to the Tie2 ligand-binding domain, the mechanisms for Tie2 chored to the extracellular matrix (ECM) by Ang1-induced Tie2 cis-association (10, 18). Integrins also have been implicated in activation are poorly understood. We report here the structural α β – basis of Ang1-induced Tie2 dimerization in cis and provide Tie2 signaling, and the 5 1 integrin heterodimer enhances Ang1-induced EC adhesion and Tie2 activation (13, 19, 20). -
Supplementary Data ASXL2 Regulates Hematopoiesis in Mice and Its
Supplementary data ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion Supplementary Methods Genomic DNA extraction Genomic DNA was extracted from BM mononuclear cells using a DNA extraction kit (Puregene Gentra System, Minneapolis, MN, USA) according to the manufacturer’s instructions. Genomic DNA was quantified using Qubit Fluorometer (Life Technologies) and DNA integrity was assessed by agarose gel electrophoresis. For samples with low quantity, DNA was amplified using REPLI-g Ultrafast mini kit (Qiagen). Peripheral blood analysis Complete peripheral blood counts were analysed using Abbott Cell-Dyn 3700 hematology analyzer (Abbott Laboratories). Expression analysis of Asxl2 and Asxl1 Transcript levels of Asxl2 and Asxl1 were estimated using quantitative RT-PCR with following primers: Asxl2 primer set 1, ATTCGACAAGAGATTGAGAAGGAG (forward) and TTTCTGTGAATCTTCAAGGCTTAG (reverse); Asxl2 primer set 2, GCCCTTAACAATGAGTTCTTCACT (forward) and TCCACAGCTCTACTTTCTTCTCCT (reverse); Asxl1 primers, GGTGGAACAATGGAAGGAAA (forward) and CTGGCCGAGAACGTTTCTTA (reverse). Asxl2 protein was detected in immunoblot using anti-ASXL2 antibody (Bethyl). In vitro differentiation of bone marrow cells Bone marrow (BM) cells were cultured in IMDM containing 20% FBS and 10 ng/ml IL3, 10 ng/ml IL6, 20 ng/ml SCF and 20 ng/ml GMCSF for two weeks. For FACS analysis, cells were washed, stained with fluorochrome-conjugated antibodies and analysed on FACS LSR II flow cytometer (BD Biosciences) using FACSDIVA software (BD Biosciences). Colony re-plating assay Bone marrow cells were plated in methylcellulose medium containing mouse stem cell factor (SCF), mouse interleukin 3 (IL-3), human interleukin 6 (IL-6) and human erythropoietin (MethoCult GF M3434; StemCell Technologies). Colonies were enumerated after 9-12 days and cells were harvested for re-plating. -
(Erdafitinib), a Functionally Selective Small Molecule FGFR Family Inhibitor
Author Manuscript Published OnlineFirst on March 24, 2017; DOI: 10.1158/1535-7163.MCT-16-0589 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Discovery and pharmacological characterization of JNJ-42756493 (erdafitinib), a functionally selective small molecule FGFR family inhibitor Timothy P.S. Perera1, Eleonora Jovcheva1, Laurence Mevellec2, Jorge Vialard1, Desiree De Lange1, Tinne Verhulst1, Caroline Paulussen1, Kelly Van De Ven1, Peter King1, Eddy Freyne1, David C. Rees3, Matthew Squires3, Gordon Saxty3, Martin Page1, Christopher W. Murray3, Ron Gilissen1, George Ward3, Neil T. Thompson3, David R. Newell4, Na Cheng5, Liang Xie5, Jennifer Yang5, Suso J. Platero6, Jayaprakash D. Karkera6, Christopher Moy6, Patrick Angibaud2, Sylvie Laquerre6 and Matthew V. Lorenzi6,7. 1Janssen Research and Development, Beerse, Belgium. 2Janssen Research and Development, Val de Reuil, France. 3Astex Pharmaceuticals, Cambridge, United Kingdom. 4Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK. 5Janssen Research and Development, Shanghai, China. 6Janssen Research and Development, Spring House, USA. 7To whom correspondence should be addressed: Matthew V. Lorenzi, Oncology Discovery, Janssen R&D, 1400 McKean Road, Spring House, PA 19477. Phone: 215 793-7356; E-mail: [email protected] Disclosure of Potential Conflicts of Interest: T.P.S. Perera, E. Jovcheva, L. Mevellec, J. Vialard, D. De Lange, T. Verhulst, C. Paulussen, K. Van De Ven, P. King, E. Freyne, M. Page, R. Gilissen, N. Cheng, L. Xie, J. Yang, S.J. Platero, J.D. Karkera, C. Moy, P. Angibaud, S. Laquerre and M.V. Lorenzi are or have been employees of Janssen R&D, and D.C. -
Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor
Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Kim, H., L. Tan, E. L. Weisberg, F. Liu, P. Canning, H. G. Choi, S. A. Ezell, et al. 2013. “Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor.” ACS Chemical Biology 8 (10): 2145-2150. doi:10.1021/cb400430t. http://dx.doi.org/10.1021/ cb400430t. Published Version doi:10.1021/cb400430t Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12152819 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Letters pubs.acs.org/acschemicalbiology Terms of Use CC-BY Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor † # ‡ § # ‡ # ∥ ‡ # ⊥ # Hyung-Gu Kim, , Li Tan, , , Ellen L. Weisberg, , Feiyang Liu, , , Peter Canning, , ‡ # † ∥ ‡ ∥ ‡ § † Hwan Geun Choi, , Scott A. Ezell, Hong Wu, , Zheng Zhao, Jinhua Wang, , Anna Mandinova, ‡ ⊥ ∥ ‡ † ‡ § James D. Griffin, Alex N. Bullock, Qingsong Liu,*, , Sam W. Lee,*, and Nathanael S. Gray*, , † Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States ‡ § Dana Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States ∥ High Magnetic Field laboratory, Chinese Academy of Sciences, P.O. Box 1110, Hefei, Anhui, 230031, P. R. China ⊥ Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, U.K. -
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. -
Amplification of the Human Epidermal Growth Factor Receptor 2 (HER2) Gene Is Associated with a Microsatellite Stable Status in Chinese Gastric Cancer Patients
387 Original Article Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with a microsatellite stable status in Chinese gastric cancer patients He Huang1#, Zhengkun Wang2#, Yi Li2, Qun Zhao3, Zhaojian Niu2 1Department of Gastrointestinal Surgery, The First Hospital of Shanxi Medical University, Shanxi, China; 2Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China; 3Department of Gastrosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China Contributions: I) Conception and design: Z Niu, Q Zhao, H Huang; (II) Administrative support: Z Niu, H Huang, Z Wang; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: Z Wang, Q Zhao; (V) Data analysis and interpretation: Z Niu, H Huang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Zhaojian Niu. Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao 260003, China. Email: [email protected]; Qun Zhao. Department of Gastrosurgery, The Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Shijiazhuang 050011, China. Email: [email protected]. Background: Gastric cancer (GC) is one of the most common cancers worldwide. However, little is known about the combination of HER2 amplification and microsatellite instability (MSI) status in GC. This study aimed to analyze the correlation of HER2 amplification with microsatellite instability (MSI) status, clinical characteristics, and the tumor mutational burden (TMB) of patients. Methods: A total of 192 gastric cancer (GC) patients were enrolled in this cohort. To analyze genomic alterations (GAs), deep sequencing was performed on 450 target cancer genes.