SHOC2 Phosphatase-Dependent RAF Dimerization Mediates Resistance to MEK Inhibition in RAS-Mutant Cancers
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SHOC2–MRAS–PP1 Complex Positively Regulates RAF Activity and Contributes to Noonan Syndrome Pathogenesis
SHOC2–MRAS–PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis Lucy C. Younga,1, Nicole Hartiga,2, Isabel Boned del Ríoa, Sibel Saria, Benjamin Ringham-Terrya, Joshua R. Wainwrighta, Greg G. Jonesa, Frank McCormickb,3, and Pablo Rodriguez-Vicianaa,3 aUniversity College London Cancer Institute, University College London, London WC1E 6DD, United Kingdom; and bHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158 Contributed by Frank McCormick, September 18, 2018 (sent for review November 22, 2017; reviewed by Deborah K. Morrison and Marc Therrien) Dephosphorylation of the inhibitory “S259” site on RAF kinases CRAF/RAF1 mutations are also frequently found in NS and (S259 on CRAF, S365 on BRAF) plays a key role in RAF activation. cluster around the S259 14-3-3 binding site, enhancing CRAF ac- The MRAS GTPase, a close relative of RAS oncoproteins, interacts tivity through disruption of 14-3-3 binding (8) and highlighting the with SHOC2 and protein phosphatase 1 (PP1) to form a heterotri- key role of this regulatory step in RAF–ERK pathway activation. meric holoenzyme that dephosphorylates this S259 RAF site. MRAS is a very close relative of the classical RAS oncoproteins MRAS and SHOC2 function as PP1 regulatory subunits providing (H-, N-, and KRAS, hereafter referred to collectively as “RAS”) the complex with striking specificity against RAF. MRAS also func- and shares most regulatory and effector interactions as well as tions as a targeting subunit as membrane localization is required transforming ability (9–11). However, MRAS also has specific for efficient RAF dephosphorylation and ERK pathway regulation functions of its own, and uniquely among RAS family GTPases, it in cells. -
Biocreative 2012 Proceedings
Proceedings of 2012 BioCreative Workshop April 4 -5, 2012 Washington, DC USA Editors: Cecilia Arighi Kevin Cohen Lynette Hirschman Martin Krallinger Zhiyong Lu Carolyn Mattingly Alfonso Valencia Thomas Wiegers John Wilbur Cathy Wu 2012 BioCreative Workshop Proceedings Table of Contents Preface…………………………………………………………………………………….......... iv Committees……………………………………………………………………………………... v Workshop Agenda…………………………………………………………………………….. vi Track 1 Collaborative Biocuration-Text Mining Development Task for Document Prioritization for Curation……………………………………..……………………………………………….. 2 T Wiegers, AP Davis, and CJ Mattingly System Description for the BioCreative 2012 Triage Task ………………………………... 20 S Kim, W Kim, CH Wei, Z Lu and WJ Wilbur Ranking of CTD articles and interactions using the OntoGene pipeline ……………..….. 25 F Rinaldi, S Clematide and S Hafner Selection of relevant articles for curation for the Comparative Toxicogenomic Database…………………………………………………………………………………………. 31 D Vishnyakova, E Pasche and P Ruch CoIN: a network exploration for document triage………………………………................... 39 YY Hsu and HY Kao DrTW: A Biomedical Term Weighting Method for Document Recommendation ………... 45 JH Ju, YD Chen and JH Chiang C2HI: a Complete CHemical Information decision system……………………………..….. 52 CH Ke, TLM Lee and JH Chiang Track 2 Overview of BioCreative Curation Workshop Track II: Curation Workflows….…………... 59 Z Lu and L Hirschman WormBase Literature Curation Workflow ……………………………………………………. 66 KV Auken, T Bieri, A Cabunoc, J Chan, Wj Chen, P Davis, A Duong, R Fang, C Grove, Tw Harris, K Howe, R Kishore, R Lee, Y Li, Hm Muller, C Nakamura, B Nash, P Ozersky, M Paulini, D Raciti, A Rangarajan, G Schindelman, Ma Tuli, D Wang, X Wang, G Williams, K Yook, J Hodgkin, M Berriman, R Durbin, P Kersey, J Spieth, L Stein and Pw Sternberg Literature curation workflow at The Arabidopsis Information Resource (TAIR)…..……… 72 D Li, R Muller, TZ Berardini and E Huala Summary of Curation Process for one component of the Mouse Genome Informatics Database Resource ………………………………………………………………………….... -
Is the Proteome of Bronchoalveolar Lavage Extracellular Vesicles a Marker of Advanced Lung Cancer?
cancers Article Is the Proteome of Bronchoalveolar Lavage Extracellular Vesicles a Marker of Advanced Lung Cancer? Ana Sofia Carvalho 1,* , Maria Carolina Strano Moraes 2, Chan Hyun Na 3, Ivo Fierro-Monti 1 , Andreia Henriques 1 , Sara Zahedi 1, Cristian Bodo 2, Erin M Tranfield 4, Ana Laura Sousa 4 , Ana Farinho 5, Luís Vaz Rodrigues 6, Paula Pinto 7 , Cristina Bárbara 8 , Leonor Mota 7, Tiago Tavares de Abreu 7,Júlio Semedo 7, Susana Seixas 9 , Prashant Kumar 10,11 , Bruno Costa-Silva 2 , Akhilesh Pandey 10,11,12 and Rune Matthiesen 1,* 1 Computational and Experimental Biology Group, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade NOVA de Lisboa, Campo dos Martires da Patria, 130, 1169-056 Lisboa, Portugal; ivo.fi[email protected] (I.F.-M.); [email protected] (A.H.); [email protected] (S.Z.) 2 Systems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown, Av. Brasilia, Doca de Pedroucos, 1400-038 Lisbon, Portugal; [email protected] (M.C.S.M.); [email protected] (C.B.); [email protected] (B.C.-S.) 3 Department of Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; [email protected] 4 Electron Microscopy Facility, Instituto Gulbenkian de Ciência—Rua da Quinta Grande, 6, 2780-156 Oeiras, Portugal; etranfi[email protected] (E.M.T.); [email protected] (A.L.S.) 5 iNOVA4Health—Advancing Precision Medicine, -
October 1, 2014 the Following Document Describes Findings from Genetic Research Performed at the Hudsonalpha Institute for Biote
601 Genome Way Huntsville, AL 35806 hudsonalpha.org October 1, 2014 The following document describes findings from genetic research performed at the HudsonAlpha Institute for Biotechnology through the Genomic Diagnosis in Children with Developmental Delay project (protocol no. 20130675). These results were verified by a CLIA-certified laboratory, but the DNA isolation was carried out in a research setting (at HudsonAlpha) and therefore the results cannot be considered CLIA-certified. Family study ID#: 000XX-C Affected child, year of birth: XXXX Affected child, gender: Male Relationship to affected child: Self Indication for testing: Based on the information provided to the research laboratory, the affected child has a history of developmental delay, pulmonary stenosis, growth hormone deficiency, and dysmorphic features. Prior genetic testing has included Noonan syndrome (PTPN11 gene sequencing). Primary Result: Causative (pathogenic) variant found Gene Variant Zygosity Classificationi Disease Inheritance SHOC2 chromosome 10 Heterozygous 5 = Pathogenic Noonan-like Autosomal (one copy) syndrome with dominant pos 112724120 loose anagen (de novo) c.4A>G,p.S2G hair The genetic variant listed above was detected in one copy of this your son’s SHOC2 gene. This variant is thought to be pathogenic (the likely cause of symptoms). Variations in the SHOC2 gene are known to be associated with a subtype of Noonan syndrome, characterized by typical Noonan syndrome features in addition to sparse, slow growing hair. Classic Noonan syndrome is caused by a genetic change in a set of other genes including PTPN11, SOS1 and RAF1. Your son has previously been tested for genetic changes in one ore more of these more commonly associated genes. -
Changes in Prostate Gene Expression in Men Undergoing an Intensive Nutrition and Lifestyle Intervention
Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention Dean Ornish*†‡, Mark Jesus M. Magbanua§, Gerdi Weidner*, Vivian Weinberg¶, Colleen Kemp*, Christopher Green§, Michael D. Mattie§, Ruth Marlin*, Jeff Simkoʈ, Katsuto Shinohara§, Christopher M. Haqq§ and Peter R. Carroll§ §Department of Urology, The Helen Diller Family Comprehensive Cancer Center, and ʈDepartment of Pathology, University of California, 2340 Sutter Street, San Francisco, CA 94115; *Preventive Medicine Research Institute, 900 Bridgeway, Sausalito, CA 94965; †Department of Medicine, School of Medicine, University of California, 505 Parnassus Avenue, San Francisco, CA 94143; and ¶Biostatistics Core, The Helen Diller Family Comprehensive Cancer Center, University of California, 513 Parnassus Avenue, Box 0127, San Francisco, CA 94143 Communicated by J. Craig Venter, The J. Craig Venter Institute, Rockville, MD, April 2, 2008 (received for review February 13, 2008) Epidemiological and prospective studies indicate that comprehensive indolent low-risk prostate cancers, defined by strict clinical and lifestyle changes may modify the progression of prostate cancer. pathologic criteria designed to minimize the risk for metastatic However, the molecular mechanisms by which improvements in diet disease as a result of study participation (9). The 30 men who and lifestyle might affect the prostate microenvironment are poorly enrolled did not undergo surgery or radiation therapy to treat their understood. We conducted a pilot study to examine changes in low-risk tumors; rather, they underwent comprehensive lifestyle prostate gene expression in a unique population of men with low-risk changes (low-fat, whole-foods, plant-based nutrition; stress man- prostate cancer who declined immediate surgery, hormonal therapy, agement techniques; moderate exercise; and participation in a or radiation and participated in an intensive nutrition and lifestyle psychosocial group support). -
Dissecting the Genetic Etiology of Lupus at ETS1 Locus
Dissecting the Genetic Etiology of Lupus at ETS1 Locus A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Immunobiology of the College of Medicine 2017 by Xiaoming Lu B.S. Sun Yat-sen University, P.R. China June 2011 Dissertation Committee: John B. Harley, MD, PhD Harinder Singh, PhD Leah C. Kottyan, PhD Matthew T. Weirauch, PhD Kasper Hoebe, PhD Lili Ding, PhD i Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong evidence for genetics factor involvement. Genome-wide association studies have identified 84 risk loci associated with SLE. However, the specific genotype-dependent (allelic) molecular mechanisms connecting these lupus-genetic risk loci to immunological dysregulation are mostly still unidentified. ~ 90% of these loci contain variants that are non-coding, and are thus likely to act by impacting subtle, comparatively hard to predict mechanisms controlling gene expression. Here, we developed a strategic approach to prioritize non-coding variants, and screen them for their function. This approach involves computational prioritization using functional genomic databases followed by experimental analysis of differential binding of transcription factors (TFs) to risk and non-risk alleles. For both electrophoretic mobility shift assay (EMSA) and DNA affinity precipitation assay (DAPA) analysis of genetic variants, a synthetic DNA oligonucleotide (oligo) is used to identify factors in the nuclear lysate of disease or phenotype-relevant cells. This strategic approach was then used for investigating SLE association at ETS1 locus. Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. -
Pathogenetics of the Rasopathies William E
HMG Advance Access published July 24, 2016 Human Molecular Genetics, 2016, Vol. 0, No. 0 1–10 doi: 10.1093/hmg/ddw191 Advance Access Publication Date: 12 July 2016 Invited Review INVITED REVIEW Downloaded from Pathogenetics of the RASopathies William E. Tidyman1,3 and Katherine A. Rauen2,3,* 1Division of Behavioral and Developmental Pediatrics, Department of Pediatrics, 2Department of Pediatrics, http://hmg.oxfordjournals.org/ Division of Genomic Medicine, University of California Davis, Sacramento, CA, USA and 3UC Davis MIND Institute, Sacramento, CA 95817, USA *To whom correspondence should be addressed at: UC Davis MIND Institute, 2825 50th Street, Room 2284, Sacramento, CA 95817, USA. Tel: 916 7030204; Fax: 916 7030243; Email: [email protected] Abstract at Serial AcquisitionsEdith Cowan University, Library - Level 2 on August 22, 2016 The RASopathies are defined as a group of medical genetics syndromes that are caused by germ-line mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. Taken together, the RASopathies represent one of the most prevalent groups of malformation syndromes affecting greater than 1 in 1,000 individ- uals. The Ras/MAPK pathway has been well studied in the context of cancer as it plays essential roles in growth, differentia- tion, cell cycle, senescence and apoptosis, all of which are also critical to normal development. The consequence of germ-line dysregulation leads to phenotypic alterations of development. RASopathies can be caused by several pathogenetic mecha- nisms that ultimately impact or alter the normal function and regulation of the MAPK pathway. These pathogenetic mecha- nisms can include functional alteration of GTPases, Ras GTPase-activating proteins, Ras guanine exchange factors, kinases, scaffolding or adaptor proteins, ubiquitin ligases, phosphatases and pathway inhibitors. -
SHOC2 Complex-Driven RAF Dimerization Selectively Contributes to ERK Pathway Dynamics
SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics Isabel Boned del Ríoa,1, Lucy C. Younga,1, Sibel Saria, Greg G. Jonesa, Benjamin Ringham-Terrya, Nicole Hartiga, Ewa Rejnowicza, Winnie Leia, Amandeep Bhamrab, Silvia Surinovab, and Pablo Rodriguez-Vicianaa,2 aUniversity College London Cancer Institute, University College London, WC1E 6DD London, United Kingdoms; and bProteomics Research Core Facility, University College London Cancer Institute, WC1E 6DD London, United Kingdom Edited by Roger J. Davis, Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, MA, and approved May 28, 2019 (received for review February 21, 2019) Despite the crucial role of RAF kinases in cell signaling and harness the addiction of RAS mutant cancers to ERK signaling disease, we still lack a complete understanding of their regulation. into viable therapies, new strategies to inhibit the pathway with Heterodimerization of RAF kinases as well as dephosphorylation improved therapeutic margins are needed, for example by inhib- of a conserved “S259” inhibitory site are important steps for RAF ac- iting ERK signaling in a context- or compartment-dependent tivation but the precise mechanisms and dynamics remain unclear. A manner (9, 10). ternary complex comprised of SHOC2, MRAS, and PP1 (SHOC2 com- MEK and ERK kinases are fully activated by phosphorylation plex) functions as a RAF S259 holophosphatase and gain-of-function in two sites within its kinase domain by RAF and MEK, re- mutations in SHOC2, MRAS, and PP1 that promote complex forma- spectively. On the other hand, RAF activation is a complex mul- tion are found in Noonan syndrome. -
MRAS: a Close but Understudied Member of the RAS Family
Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press MRAS: A Close but Understudied Member of the RAS Family Lucy C. Young1 and Pablo Rodriguez-Viciana2 1UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94158 2UCL Cancer Institute, Paul O’Gorman Building, University College London, London WC1E 6BT, United Kingdom Correspondence: [email protected] MRAS is the closest relative to the classical RAS oncoproteins and shares most regulatory and effector interactions. However, it also has unique functions, including its ability to function as a phosphatase regulatory subunit when in complex with SHOC2 and protein phosphatase 1 (PP1). This phosphatase complex regulates a crucial step in the activation cycle of RAF kinases and provides a key coordinate input required for efficient ERK pathway activation and trans- formation by RAS. MRAS mutations rarely occur in cancer but deregulated expression may play a role in tumorigenesis in some settings. Activating mutations in MRAS (as well as SHOC2 and PP1) do occur in the RASopathy Noonan syndrome, underscoring a key role for MRAS within the RAS-ERK pathway. MRAS also has unique roles in cell migration and differentiation and has properties consistent with a key role in the regulation of cell polarity. Further inves- tigations should shed light on what remains a relatively understudied RAS family member. he RRAS subgroup (RRAS, TC21/RRAS2, SEQUENCE FEATURES OF MRAS Tand MRAS/RRAS3) of the RAS family GTPases (RFGs) are the closest relatives to the The RRAS subgroup lies within a distinct classical RAS oncogenes (H/N/KRAS, hereafter branch of the tree of all small GTPases with referred to collectively as RAS). -
Pathway and Network Analysis for Mrna and Protein Profiling Data
Pathway and network analysis for mRNA and protein profiling data Bing Zhang, Ph.D. Professor of Molecular and Human Genetics Lester & Sue Smith Breast Center Baylor College of Medicine [email protected] VU workshop, 2016 Gene expression DNA Transcription Transcriptome Transcriptome RNA mRNA decay profiling Translation Proteome Protein Proteome Protein degradation profiling Phenotype Networks VU workshop, 2016 Overall workflow of gene expression studies Biological question Experimental design Microarray RNA-Seq Shotgun proteomics Image analysis Reads mapping Peptide/protein ID Signal intensities Read counts Spectral counts; Intensities Data Analysis Experimental Hypothesis validation VU workshop, 2016 Data matrix Samples probe_set_id HNE0_1 HNE0_2 HNE0_3 HNE60_1 HNE60_2 HNE60_3 1007_s_at 8.6888 8.5025 8.5471 8.5412 8.5624 8.3073 1053_at 9.1558 9.1835 9.4294 9.2111 9.1204 9.2494 117_at 7.0700 7.0034 6.9047 9.0414 8.6382 9.2663 121_at 9.7174 9.7440 9.6120 9.7581 9.7422 9.7345 1255_g_at 4.2801 4.4669 4.2360 4.3700 4.4573 4.2979 1294_at 6.3556 6.2381 6.2053 6.4290 6.5074 6.2771 Genes 1316_at 6.5759 6.5330 6.4709 6.6636 6.6438 6.4688 1320_at 6.5497 6.5388 6.5410 6.6605 6.5987 6.7236 1405_i_at 4.3260 4.4640 4.1438 4.3462 4.3876 4.6849 1431_at 5.2191 5.2070 5.2657 5.2823 5.2522 5.1808 1438_at 7.0155 6.9359 6.9241 7.0248 7.0142 7.0971 1487_at 8.6361 8.4879 8.4498 8.4470 8.5311 8.4225 1494_f_at 7.3296 7.3901 7.0886 7.2648 7.6058 7.2949 1552256_a_at 10.6245 10.5235 10.6522 10.4205 10.2344 10.3144 1552257_a_at 10.3224 10.1749 10.1992 10.2464 10.2191 -
KRAS Interaction with RAF1 RAS-Binding Domain and Cysteine-Rich Domain Provides Insights Into RAS-Mediated RAF Activation
bioRxiv preprint doi: https://doi.org/10.1101/2020.07.31.231134; this version posted July 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation Timothy H. Tran1,§, Albert H. Chan1,§, Lucy C. Young2,§, Lakshman Bindu1, Chris Neale3, Simon Messing1, Srisathiyanarayanan Dharmaiah1, Troy Taylor1, John-Paul Denson1, Dominic Esposito1, Dwight V. Nissley1, Andrew G. Stephen1, Frank McCormick1,2, #, Dhirendra K. Simanshu1, # 1NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702. 2Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158. 3Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico §These authors contributed equally to this work. #To whom correspondence should be addressed: Dhirendra Simanshu (Email: [email protected], Phone: 301-360-3438) Frank McCormick (Email: [email protected], Phone: 415-218-0155) Running title: KRAS compleXed with RAF1(RBDCRD) Keywords: RAS, RAS-RAF compleX, Crystal structure, RBDCRD, RAF kinase, CRAF 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.31.231134; this version posted July 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT A vital first step of RAF activation involves binding to active RAS, resulting in the recruitment of RAF to the plasma membrane. -
Next-Generation Sequencing Identifies Rare Variants Associated with Noonan Syndrome
Next-generation sequencing identifies rare variants associated with Noonan syndrome Peng-Chieh Chena,b,c, Jiani Yind, Hui-Wen Yuc, Tao Yuanb, Minerva Fernandezd, Christina K. Yunge, Quang M. Trinhe, Vanya D. Peltekovae, Jeffrey G. Reidf, Erica Tworog-Dubeb, Margaret B. Morganf, Donna M. Muznyf, Lincoln Steine, John D. McPhersone, Amy E. Robertsg, Richard A. Gibbsf, Benjamin G. Neeld,1,2, and Raju Kucherlapatia,b,1,2 aDepartment of Genetics, Harvard Medical School, Boston, MA 02115; bDepartment of Medicine, Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115; cInstitute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70457, Taiwan; dPrincess Margaret Cancer Center, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 1L7; eOntario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3; fHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030; and gDepartment of Cardiology and Division of Genetics, Department of Medicine, Boston Children’s Hospital Boston, Boston, MA 02115 Edited by J. G. Seidman, Harvard Medical School, Boston, MA, and approved June 12, 2014 (received for review January 16, 2014) Noonan syndrome (NS) is a relatively common genetic disorder, NS, the most common RASopathy, occurs in familial and spo- characterized by typical facies, short stature, developmental delay, radic forms and is characterized by typical facies, short stature, and cardiac abnormalities. Known causative genes account for 70– variable developmental delay, cognitive defects, and cardiac ab- 80% of clinically diagnosed NS patients, but the genetic basis for normalities. Webbed neck, pectus abnormalities, coagulation the remaining 20–30% of cases is unknown.