The Proximal Signaling Network of the BCR-ABL1 Oncogene Shows a Modular Organization
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Mutation-Specific and Common Phosphotyrosine Signatures of KRAS G12D and G13D Alleles Anticipated Graduation August 1St, 2018
MUTATION-SPECIFIC AND COMMON PHOSPHOTYROSINE SIGNATURES OF KRAS G12D AND G13D ALLELES by Raiha Tahir A dissertation submitted to The Johns Hopkins University in conformity with the requirement of the degree of Doctor of Philosophy Baltimore, MD August 2018 © 2018 Raiha Tahir All Rights Reserved ABSTRACT KRAS is one of the most frequently mutated genes across all cancer subtypes. Two of the most frequent oncogenic KRAS mutations observed in patients result in glycine to aspartic acid substitution at either codon 12 (G12D) or 13 (G13D). Although the biochemical differences between these two predominant mutations are not fully understood, distinct clinical features of the resulting tumors suggest involvement of disparate signaling mechanisms. When we compared the global phosphotyrosine proteomic profiles of isogenic colorectal cancer cell lines bearing either G12D or G13D KRAS mutations, we observed both shared as well as unique signaling events induced by the two KRAS mutations. Remarkably, while the G12D mutation led to an increase in membrane proximal and adherens junction signaling, the G13D mutation led to activation of signaling molecules such as non-receptor tyrosine kinases, MAPK kinases and regulators of metabolic processes. The importance of one of the cell surface molecules, MPZL1, which found to be hyperphosphorylated in G12D cells, was confirmed by cellular assays as its knockdown led to a decrease in proliferation of G12D but not G13D expressing cells. Overall, our study reveals important signaling differences across two common KRAS mutations and highlights the utility of our approach to systematically dissect the subtle differences between related oncogenic mutants and potentially lead to individualized treatments. -
Defining Functional Interactions During Biogenesis of Epithelial Junctions
ARTICLE Received 11 Dec 2015 | Accepted 13 Oct 2016 | Published 6 Dec 2016 | Updated 5 Jan 2017 DOI: 10.1038/ncomms13542 OPEN Defining functional interactions during biogenesis of epithelial junctions J.C. Erasmus1,*, S. Bruche1,*,w, L. Pizarro1,2,*, N. Maimari1,3,*, T. Poggioli1,w, C. Tomlinson4,J.Lees5, I. Zalivina1,w, A. Wheeler1,w, A. Alberts6, A. Russo2 & V.M.M. Braga1 In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases. 1 National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. 2 Computing Department, Imperial College London, London SW7 2AZ, UK. 3 Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK. 4 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. -
Molecular Cytogenetics Biomed Central
Molecular Cytogenetics BioMed Central Research Open Access FISH mapping of Philadelphia negative BCR/ABL1 positive CML Anna Virgili1, Diana Brazma1, Alistair G Reid2, Julie Howard-Reeves1, Mikel Valgañón1, Anastasios Chanalaris1, Valeria AS De Melo2, David Marin2, Jane F Apperley2, Colin Grace1 and Ellie P Nacheva*1 Address: 1Molecular Cytogenetics, Academic Haematology, Royal Free and UCL Medical School, Rowland Hill Street, London, NW3 2PF, UK and 2Imperial College, Faculty Medicine, Hammersmith Hospital, Dept of Haematology, Du Cane Road, London, W12 ONN, UK Email: Anna Virgili - [email protected]; Diana Brazma - [email protected]; Alistair G Reid - [email protected]; Julie Howard-Reeves - [email protected]; Mikel Valgañón - [email protected]; Anastasios Chanalaris - [email protected]; Valeria AS De Melo - [email protected]; David Marin - [email protected]; Jane F Apperley - [email protected]; Colin Grace - [email protected]; Ellie P Nacheva* - [email protected] * Corresponding author Published: 18 July 2008 Received: 21 May 2008 Accepted: 18 July 2008 Molecular Cytogenetics 2008, 1:14 doi:10.1186/1755-8166-1-14 This article is available from: http://www.molecularcytogenetics.org/content/1/1/14 © 2008 Virgili et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Chronic myeloid leukaemia (CML) is a haematopoietic stem cell disorder, almost always characterized by the presence of the Philadelphia chromosome (Ph), usually due to t(9;22)(q34;q11) or its variants. -
Host-Pathogen Systems Biology: Logical Modelling of Hepatocyte
BMC Systems Biology BioMed Central Research article Open Access Host-pathogen systems biology: logical modelling of hepatocyte growth factor and Helicobacter pylori induced c-Met signal transduction Raimo Franke†1, Melanie Müller†1, Nicole Wundrack1, Ernst-Dieter Gilles2, Steffen Klamt2, Thilo Kähne1 and Michael Naumann*1 Address: 1Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany and 2Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstrasse 1, 39106 Magdeburg, Germany Email: Raimo Franke - [email protected]; Melanie Müller - [email protected]; Nicole Wundrack - [email protected]; Ernst-Dieter Gilles - [email protected]; Steffen Klamt - Klamt@mpi- magdeburg.mpg.de; Thilo Kähne - [email protected]; Michael Naumann* - [email protected] * Corresponding author †Equal contributors Published: 14 January 2008 Received: 3 October 2007 Accepted: 14 January 2008 BMC Systems Biology 2008, 2:4 doi:10.1186/1752-0509-2-4 This article is available from: http://www.biomedcentral.com/1752-0509/2/4 © 2008 Franke et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of tissues, including epithelial cells, on binding to the receptor tyrosine kinase c-Met. Abnormal c-Met signalling contributes to tumour genesis, in particular to the development of invasive and metastatic phenotypes. -
CD93 and Dystroglycan Cooperation in Human Endothelial Cell Adhesion and Migration
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 9 CD93 and dystroglycan cooperation in human endothelial cell adhesion and migration Federico Galvagni1,*, Federica Nardi1,*, Marco Maida1, Giulia Bernardini1, Silvia Vannuccini2, Felice Petraglia2, Annalisa Santucci1, Maurizio Orlandini1 1 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 2-53100 Siena, Italy 2 Department of Molecular and Developmental Medicine, Obstetrics and Gynecology, University of Siena, 53100 Siena, Italy *These authors contributed equally to this work Correspondence to: Maurizio Orlandini, e-mail: [email protected] Keywords: angiogenesis, signal transduction, C1qRp, Src, Cbl Received: June 29, 2015 Accepted: January 22, 2016 Published: February 02, 2016 ABSTRACT CD93 is a transmembrane glycoprotein predominantly expressed in endothelial cells. Although CD93 displays proangiogenic activity, its molecular function in angiogenesis still needs to be clarified. To get molecular insight into the biological role of CD93 in the endothelium, we performed proteomic analyses to examine changes in the protein profile of endothelial cells after CD93 silencing. Among differentially expressed proteins, we identified dystroglycan, a laminin-binding protein involved in angiogenesis, whose expression is increased in vascular endothelial cells within malignant tumors. Using immunofluorescence, FRET, and proximity ligation analyses, we observed a close interaction between CD93 and β-dystroglycan. Moreover, silencing experiments showed that CD93 and dystroglycan promoted endothelial cell migration and organization into capillary-like structures. CD93 proved to be phosphorylated on tyrosine 628 and 644 following cell adhesion on laminin through dystroglycan. This phosphorylation was shown to be necessary for a proper endothelial migratory phenotype. Moreover, we showed that during cell spreading phosphorylated CD93 recruited the signaling protein Cbl, which in turn was phosphorylated on tyrosine 774. -
RET/PTC Activation in Papillary Thyroid Carcinoma
European Journal of Endocrinology (2006) 155 645–653 ISSN 0804-4643 INVITED REVIEW RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture Massimo Santoro1, Rosa Marina Melillo1 and Alfredo Fusco1,2 1Istituto di Endocrinologia ed Oncologia Sperimentale del CNR ‘G. Salvatore’, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, University ‘Federico II’, Via S. Pansini, 5, 80131 Naples, Italy and 2NOGEC (Naples Oncogenomic Center)–CEINGE, Biotecnologie Avanzate & SEMM, European School of Molecular Medicine, Naples, Italy (Correspondence should be addressed to M Santoro; Email: [email protected]) Abstract Papillary thyroid carcinoma (PTC) is frequently associated with RET gene rearrangements that generate the so-called RET/PTC oncogenes. In this review, we examine the data about the mechanisms of thyroid cell transformation, activation of downstream signal transduction pathways and modulation of gene expression induced by RET/PTC. These findings have advanced our understanding of the processes underlying PTC formation and provide the basis for novel therapeutic approaches to this disease. European Journal of Endocrinology 155 645–653 RET/PTC rearrangements in papillary growth factor, have been described in a fraction of PTC thyroid carcinoma patients (7). As illustrated in figure 1, many different genes have been found to be rearranged with RET in The rearranged during tansfection (RET) proto-onco- individual PTC patients. RET/PTC1 and 3 account for gene, located on chromosome 10q11.2, was isolated in more than 90% of all rearrangements and are hence, by 1985 and shown to be activated by a DNA rearrange- far, the most frequent variants (8–11). They result from ment (rearranged during transfection) (1).As the fusion of RET to the coiled-coil domain containing illustrated in Fig. -
Redefining the Specificity of Phosphoinositide-Binding by Human
bioRxiv preprint doi: https://doi.org/10.1101/2020.06.20.163253; this version posted June 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Redefining the specificity of phosphoinositide-binding by human PH domain-containing proteins Nilmani Singh1†, Adriana Reyes-Ordoñez1†, Michael A. Compagnone1, Jesus F. Moreno Castillo1, Benjamin J. Leslie2, Taekjip Ha2,3,4,5, Jie Chen1* 1Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; 2Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205; 3Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218; 4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205; 5Howard Hughes Medical Institute, Baltimore, MD 21205, USA †These authors contributed equally to this work. *Correspondence: [email protected]. bioRxiv preprint doi: https://doi.org/10.1101/2020.06.20.163253; this version posted June 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. ABSTRACT Pleckstrin homology (PH) domains are presumed to bind phosphoinositides (PIPs), but specific interaction with and regulation by PIPs for most PH domain-containing proteins are unclear. Here we employed a single-molecule pulldown assay to study interactions of lipid vesicles with full-length proteins in mammalian whole cell lysates. -
1 Validating Predicted Biological Effects of Alzheimer's Disease
Journal of Alzheimer’s Disease ISSN: 1387-2877 IOS Press DOI: 10.3233/JAD-2010-091711 Validating Predicted Biological Effects of Alzheimer’s Disease Associated SNPs Using CSF Biomarker Levels John S.K. Kauwea,*, Carlos Cruchagab,*, Sarah Bertelsenb, Kevin Mayob, Wayne Latua, Petra Nowotnyb, Anthony L. Hinrichsb, Anne M. Faganc, David M. Holtzmanc, Alzheimer’s Disease Neuroimaging Initiative** and Alison M. Goateb aDepartment of Biology, Brigham Young University, Provo, UT, USA bDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA cDepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA *Co-first authors with equal contributions. Running Title: Validating effects of AD risk variants Handling Associate Editor: Daniela Galimberti Accepted 16 April 2010 Correspondence to: Alison M. Goate, PhD, Samuel & Mae S. Ludwig Professor, Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA; Tel: +1 314-362-8691, Fax: +1 314-747-2983, Email: [email protected]. 1 **Some of the data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://www.loni.ucla.edu\ADNI). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. ADNI investigators include (complete listing available at http://www.loni.ucla.edu/ADNI/About/About_Investigators.shtml). 2 ABSTRACT Recent large-scale genetic studies of late-onset Alzheimer’s disease have identified risk variants in CALHM1, GAB2, and SORL1. The mechanisms by which these genes might modulate risk are not definitively known. -
Domain Requires the Gab2 Pleckstrin Homology Negative Regulation Of
Ligation of CD28 Stimulates the Formation of a Multimeric Signaling Complex Involving Grb-2-Associated Binder 2 (Gab2), Src Homology Phosphatase-2, and This information is current as Phosphatidylinositol 3-Kinase: Evidence That of October 1, 2021. Negative Regulation of CD28 Signaling Requires the Gab2 Pleckstrin Homology Domain Richard V. Parry, Gillian C. Whittaker, Martin Sims, Downloaded from Christine E. Edmead, Melanie J. Welham and Stephen G. Ward J Immunol 2006; 176:594-602; ; doi: 10.4049/jimmunol.176.1.594 http://www.jimmunol.org/content/176/1/594 http://www.jimmunol.org/ References This article cites 59 articles, 38 of which you can access for free at: http://www.jimmunol.org/content/176/1/594.full#ref-list-1 Why The JI? Submit online. by guest on October 1, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Ligation of CD28 Stimulates the Formation of a Multimeric Signaling Complex Involving Grb-2-Associated Binder 2 (Gab2), Src Homology Phosphatase-2, and Phosphatidylinositol 3-Kinase: Evidence That Negative Regulation of CD28 Signaling Requires the Gab2 Pleckstrin Homology Domain1 Richard V. -
RET Gene Fusions in Malignancies of the Thyroid and Other Tissues
G C A T T A C G G C A T genes Review RET Gene Fusions in Malignancies of the Thyroid and Other Tissues Massimo Santoro 1,*, Marialuisa Moccia 1, Giorgia Federico 1 and Francesca Carlomagno 1,2 1 Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; [email protected] (M.M.); [email protected] (G.F.); [email protected] (F.C.) 2 Institute of Endocrinology and Experimental Oncology of the CNR, 80131 Naples, Italy * Correspondence: [email protected] Received: 10 March 2020; Accepted: 12 April 2020; Published: 15 April 2020 Abstract: Following the identification of the BCR-ABL1 (Breakpoint Cluster Region-ABelson murine Leukemia) fusion in chronic myelogenous leukemia, gene fusions generating chimeric oncoproteins have been recognized as common genomic structural variations in human malignancies. This is, in particular, a frequent mechanism in the oncogenic conversion of protein kinases. Gene fusion was the first mechanism identified for the oncogenic activation of the receptor tyrosine kinase RET (REarranged during Transfection), initially discovered in papillary thyroid carcinoma (PTC). More recently, the advent of highly sensitive massive parallel (next generation sequencing, NGS) sequencing of tumor DNA or cell-free (cfDNA) circulating tumor DNA, allowed for the detection of RET fusions in many other solid and hematopoietic malignancies. This review summarizes the role of RET fusions in the pathogenesis of human cancer. Keywords: kinase; tyrosine kinase inhibitor; targeted therapy; thyroid cancer 1. The RET Receptor RET (REarranged during Transfection) was initially isolated as a rearranged oncoprotein upon the transfection of a human lymphoma DNA [1]. -
Structure and Function of Gab2 and Its Role in Cancer (Review)
MOLECULAR MEDICINE REPORTS 12: 4007-4014, 2015 Structure and function of Gab2 and its role in cancer (Review) CHEN-BO DING1, WEI-NA YU1, JI-HONG FENG2 and JUN-MIN LUO1 1Department of Immunology and Immunology Innovation Base for Postgraduate Education in Guizhou Province, Zunyi Medical University; 2Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563099, P.R. China Received September 11, 2014; Accepted May 19, 2015 DOI: 10.3892/mmr.2015.3951 Abstract. The docking proteins of the Grb-associated binder 1. Introduction (Gab) family transduce cellular signals between receptors and intracellular downstream effectors, and provide a platform Gab2 belongs to the Grb-associated binder (Gab) family of for protein-protein interactions. Gab2, a key member of the docking proteins, which also includes mammalian Gab1, Gab family of proteins, is involved in the amplification and Gab3 and Gab4, Drosophila daughter of sevenless, and integration of signal transduction, evoked by a variety of Caenorhabditis elegans suppressor of Clr-1 (1). Gab2 is extracellular stimuli, including growth factors, cytokines reported to contain a pleckstrin homology (PH) domain at and antigen receptors. Gab2 protein lacks intrinsic catalytic the N-terminus, several proline-rich motifs (PXXP) and activity; however, when phosphorylated by protein-tyrosine multiple tyrosine residues, which couple with SH2-containing kinases (PTKs), Gab2 recruits several Src homology-2 (SH2) molecules in a phosphorylation-dependent manner (1,2). The domain-containing proteins, including the SH2-containing Gab2 PH domain preferentially combines phosphatidylino- protein tyrosine phosphatase 2 (SHP2), the p85 subunit of sitol 3,4,5-P3 (PIP3) (3). In Gab2, two of the proline-rich motifs phosphoinositide-3 kinase (PI3K), phospholipase C-γ (PLCγ)1, are Grb2-Src homology (SH3) domain binding sites (4), which Crk, and GC-GAP. -
Imatinib Dependent Tyrosine Phosphorylation Profiling of Bcr-Abl
Provided by the author(s) and University College Dublin Library in accordance with publisher policies. Please cite the published version when available. Title Imatinib-dependent tyrosine phosphorylation profiling of Bcr-Abl-positive chronic myeloid leukemia cells Authors(s) Preisinger, C.; Schwarz, J. P.; Bleijerveld, O. B.; et al. Publication date 2012-08-27 Publication information Leukemia, 27 (3): 743-746 Publisher Nature Publishing Group Item record/more information http://hdl.handle.net/10197/5078 Publisher's version (DOI) 10.1038/leu.2012.243 Downloaded 2021-09-25T14:43:28Z The UCD community has made this article openly available. Please share how this access benefits you. Your story matters! (@ucd_oa) © Some rights reserved. For more information, please see the item record link above. 1 Imatinib dependent tyrosine phosphorylation profiling of Bcr-Abl 2 positive chronic myeloid leukemia cells 3 Bcr-Abl is the major cause and pathogenetic principle of chronic myeloid leukemia (CML). 4 Bcr-Abl results from a chromosomal translocation that fuses the bcr and the abl genes, 5 thereby generating a constitutively active tyrosine kinase, which stimulates several signaling 6 networks required for proliferation and survival. Bcr-Abl’s oncogenic properties comprise 7 both functions as a kinase and as a scaffold protein 1. A number of Bcr-Abl interaction 8 partners and downstream effectors have been described, improving our understanding of the 9 signaling networks deranged in CML. Brehme et al. recently defined the “core-interactome of 10 Bcr-Abl”, identifying seven major interaction partners of Bcr-Abl (GRB2, Shc1, Crk, c-Cbl, 11 p85, Sts-1, and SHIP-2) 2.