DOCSLIB.ORG

The Spectrum of Cardiac Anomalies in Noonan Syndrome As a Result of Mutations in the PTPN11 Gene

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Spectrum of Cardiac Anomalies in Noonan Syndrome As a Result of Mutations in the PTPN11 Gene ARTICLE The Spectrum of Cardiac Anomalies in Noonan Syndrome as a Result of Mutations in the PTPN11 Gene Yves Sznajer, MDa, Boris Keren, MDa, Clarisse Baumann, MDa, Sabrina Pereiraa, Corinne Alberti, PhDb, Jacques Elion, MD, PhDa, He´le`ne Cave´,MDa, Alain Verloes, MD, PhDa,c aDepartment of Medical Genetics, bClinical Epidemiology Unit, and cInstitut National de la Sante´et de la Recherche Me´dicale INSERM U676, AP-HP Robert Debre´ University Hospital, Paris, France The authors have indicated they have no financial relationships relevant to this article to disclose. ABSTRACT OBJECTIVE. Noonan syndrome is a clinically homogeneous but genetically heteroge- neous condition. Type 1 Noonan syndrome is defined by the presence of a mutation in the PTPN11 gene, which is found in ϳ40% of the cases. Phenotype www.pediatrics.org/cgi/doi/10.1542/ peds.2006-0211 descriptions and cardiac defects from cohorts with Noonan syndrome were delin- doi:10.1542/peds.2006-0211 eated in the “pregenomic era.” We report the heart defects and links to gene Dr Sznajer’s current affiliation is Clinical dysfunction in cardiac development in a large cohort of patients with type 1 Genetics Unit, Hoˆpital Universitaire des Noonan syndrome. Enfants Reine-Fabiola, Universite´Libre de Bruelles, Brussels, Belgium. METHODS. This was a retrospective, multicenter study based on clinical history, Key Words pictures, and medical and cardiologic workup over time. Data were collected by Noonan syndrome, cardiac defect, PTPN11 gene, phenotype, genotype referral geneticists. Mutation screening was performed by direct sequencing of Abbreviations exons 2, 3, 4, 7, 8, 12, and 13 and their intron-exon boundaries, which harbor NS—Noonan syndrome 98% of identified mutations the PTPN11 gene. CHD—congenital heart defect PVS—pulmonary valve stenosis RESULTS. A PTPN11 gene mutation was identified in 104 (38.25%) of 274 patients HCM—hypertrophic cardiomyopathy ASD-OS—atrial septal defect of ostium with Noonan syndrome. Heart defect was present in 85%. The most prevalent secundum type congenital heart defects were pulmonary valve stenosis (60%), atrial septal defect, VSD—ventricular septal defect RAS—rat sarcoma viral oncogene ostium secundum type (25%), and stenosis of the peripheral pulmonary arteries homolog (in at least 15%). Pulmonary valve stenosis and atrial septal defect, ostium secun- MAPK—mitogen-activated protein kinase dum type, were significantly associated with the identification of a mutation in the Egfr—epithelial growth factor receptor NFAT—nuclear factor of activated T cell PTPN11 gene. Ventricular septal defect and most left-sided heart defects showed a LEOPARD—lentigines, EKG anomalies, trend toward overrepresentation in the group without a mutation. ocular hypertelorism, pulmonary stenosis, abnormal genitalia, deafness CONCLUSION. We compared our data with previous series and integrated the compre- Accepted for publication Dec 12, 2006 hension of molecular PTPN11 gene dysfunction in heart development. Address correspondence to Alain Verloes, MD, PhD, Clinical Genetics Unit, 48 Boulevard Se´rurier, 75019 Paris Cedex 19, France. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2007 by the American Academy of Pediatrics PEDIATRICS Volume 119, Number 6, June 2007 e1325 Downloaded from by guest on January 27, 2017 OONAN SYNDROME (NS) is an autosomal dominant pered by the impossibility to check retrospectively for Nmultiple congenital anomalies syndrome that is the presence of valvular dysplasia in patients for whom characterized by minor facial anomalies (hypertelorism, only pulmonary stenosis was mentioned. For this rea- downward slant of the palpebral fissures with ptosis, and son, we decided to merge the 2 anomalies under the low-set posteriorly angulated ears), short stature, con- term PVS. genital heart defects (CHDs), and variable learning dis- Mutation screening focused on hot-spot locations in abilities. With an estimated incidence of 1 in 2000,1 NS the PTPN11 gene, which covered 98% of identified mu- turned out to be 1 of the most common genetic condi- tations.6–9 Exons 2, 3, 4, 7, 8, 12, and 13 of the PTPN11 tion in pediatrics and the second most common syndro- gene and their intron-exon boundaries were sequenced mal form of CHD, after trisomy 21.2 Type 1 NS corre- on both strands from genomic DNA for each patient on sponds to the causally homogeneous subgroup of an ABI 3100 Genetic Analyzer (Applied Biosystems, Fos- patients who have NS and are molecularly defined by ter City, CA). Mutations were identified using ABI the presence of a mutation in the PTPN11 gene. Muta- PRISM SeqScape 2.0 (Applied Biosystems) by compari- tions in PTPN11 are responsible for ϳ40% of the cases of son with the reference sequence for genomic and com- NS and for Ͼ95% of patients with LEOPARD syndrome plementary DNA sequence (GenBank accession Nos. (lentigines, EKG anomalies, ocular hypertelorism, pul- NT࿝009775.14 and NM࿝002834). monary stenosis, abnormal genitalia, deafness). The Statistical analysis for qualitative data and compari- penetrance of the mutations of PTPN11 is 100%, but son used ␹2 and exact Fisher test. Significance was de- their expressivity is variable even within families. Very termined as P Ͻ .05. Informed consent was obtained for recently, mutations in KRAS3 and SOS14,5 were shown in, inclusion and DNA screening. The ethics committee of respectively, Ͻ5% and 15% of PTPN11-negative patients AP-HP Bichat University Hospital (Paris, France) ap- with NS. PTPN11, SOS1, and KRAS are part of the RAS proved the study. signaling pathway. The causative gene(s) remains to be found for roughly half of patients with NS. RESULTS A broad spectrum of cardiac phenotypes has been A total of 291 patients with NS or LEOPARD syndrome recognized in NS. Pulmonary valve stenosis (PVS), hy- were initially enrolled in the study. The 19 patients who pertrophic cardiomyopathy (HCM) and atrial septal de- presented with cafe´-au-lait spots and/or lentigines were fect of ostium secundum type (ASD-OS) are the most found to share a small number of specific mutations. common defects in NS, but ventricular septal defect Because their clinical and molecular diagnosis was (VSD), peripheral pulmonary stenosis, atrioventricular LEOPARD syndrome, they were studied and published canal, aortic stenosis, mitral regurgitation, aortic coarc- separately.12 The final cohort of patients with NS com- tation, and coronary anomalies can also be seen in NS. prises 149 boys and 123 girls. The mean age in the cohort Previous studies of cohorts of patients with NS suggested is 7 years for the groups both with and without mutation that the prevalence of specific types of CHD was different (lower quartile: 2 years; upper quartile: 13 years). in type 1 NS and in NS without PTPN11 mutation.6–11 We A mutation in the PTPN11 gene was identified in 104 report the cardiac anomalies in a large cohort of patients (38.25%) patients. Table 1 summarizes the cardiologic with type 1 NS to delineate the spectrum of cardiac findings in patients. The c.922A3G (p.N308D) nucleo- defects that are caused by PTPN11 mutations and better tide substitution represents the most prevalent mutation understand the role of PTPN11 in heart development. (18.25%) in our patients. Table 2 presents the spectrum of CHD by functional domain, by exon, and, specifically, METHODS by those observed with the p.N308D mutation. Patients with NS or LEOPARD syndrome were recruited Among patients with a mutation, the apparent rate of through a multicenter network of clinical geneticists heart defect is 85%. Because the selection criteria for from France, Switzerland, and Belgium for molecular offering molecular testing were clinically based and po- analysis of the PTPN11 gene. The patients were entered tentially biased toward overrepresentation of CHD-bear- systematically in the study, on the basis of the order by ing patients, the true penetrance of CHDs in type 1 NS which samples arrived in the laboratory for diagnosis. can nevertheless not be established objectively. The most Checklists were systematically sent to referring geneti- prevalent CHD in type 1 NS are PVS (60%), ASD-OS cists independently and before completion of the DNA (25%), and stenosis of the peripheral pulmonary arteries screening. Call for supplementary data was not based on (in at least 15.4%). PVS and ASD-OS are significantly the identification (or not) of a mutation. Specific cardi- associated with the presence of a mutation (P Ͻ .01), ologic data were derived from records of transthoracic and coarctation of aorta and HCM are associated with echocardiography and, when available, from cardiac the absence of mutation. VSD and most left-sided heart catheterization and/or heart surgery. Because the data defects show a trend toward overrepresentation in the were mainly retrospective, distinction between PVS with group without a mutation. Comparison with previously normal valves and pulmonary valve dysplasia was ham- reported series of genotyped NS is difficult. We summa- e1326 SZNAJER et al Downloaded from by guest on January 27, 2017 TABLE 1 Comparison of CHD Frequency Between PTPN11-Positive (Type 1 NS) and PTPN11-Negative Patients in Our Cohort CHD Patient With an Patient Without an P Identified Identified PTPN11 Mutation PTPN11 Mutation (n ϭ 104), n (%) (n ϭ 168), n (%) PVS 62 (59.60) 53 (31.55) Ͻ.0001 ASD 26 (26.90) 22 (13.10) Ͻ.012 Atrioventricular canal 2 (1.90) 3 (1.80) NS HCM 12 (10.60) 38 (22.60) .022 Coarctation of aorta 1 (0.96) 10
Load more

Recommended publications
  • Intersectin 1 Forms Complexes with SGIP1 and Reps1 in Clathrin-Coated
    Biochemical and Biophysical Research Communications 402 (2010) 408–413 Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc Intersectin 1 forms complexes with SGIP1 and Reps1 in clathrin-coated pits ⇑ Oleksandr Dergai a, ,1, Olga Novokhatska a,1, Mykola Dergai a, Inessa Skrypkina a, Liudmyla Tsyba a, Jacques Moreau b, Alla Rynditch a a Department of Functional Genomics, Institute of Molecular Biology and Genetics, NASU, 150 Zabolotnogo Street, 03680 Kyiv, Ukraine b Molecular Mechanisms of Development, Jacques Monod Institute, Development and Neurobiology Program, UMR7592 CNRS – Paris Diderot University, 15 rue Hélène Brion, 75205 Paris Cedex 13, France article info abstract Article history: Intersectin 1 (ITSN1) is an evolutionarily conserved adaptor protein involved in clathrin-mediated endo- Received 7 October 2010 cytosis, cellular signaling and cytoskeleton rearrangement. ITSN1 gene is located on human chromosome Available online 12 October 2010 21 in Down syndrome critical region. Several studies confirmed role of ITSN1 in Down syndrome pheno- type. Here we report the identification of novel interconnections in the interaction network of this endo- Keywords: cytic adaptor. We show that the membrane-deforming protein SGIP1 (Src homology 3-domain growth Endocytosis factor receptor-bound 2-like (endophilin) interacting protein 1) and the signaling adaptor Reps1 (RalBP Adaptor proteins associated Eps15-homology domain protein) interact with ITSN1 in vivo. Both interactions are mediated Intersectin 1 by the SH3 domains of ITSN1 and proline-rich motifs of protein partners. Moreover complexes compris- Protein interactions SGIP1 ing SGIP1, Reps1 and ITSN1 have been identified. We also identified new interactions between SGIP1, Reps1 Reps1 and the BAR (Bin/amphiphysin/Rvs) domain-containing protein amphiphysin 1.
    [Show full text]
  • Effects and Mechanisms of Eps8 on the Biological Behaviour of Malignant Tumours (Review)
    824 ONCOLOGY REPORTS 45: 824-834, 2021 Effects and mechanisms of Eps8 on the biological behaviour of malignant tumours (Review) KAILI LUO1, LEI ZHANG2, YUAN LIAO1, HONGYU ZHOU1, HONGYING YANG2, MIN LUO1 and CHEN QING1 1School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500; 2Department of Gynecology, Yunnan Tumor Hospital and The Third Affiliated Hospital of Kunming Medical University; Kunming, Yunnan 650118, P.R. China Received August 29, 2020; Accepted December 9, 2020 DOI: 10.3892/or.2021.7927 Abstract. Epidermal growth factor receptor pathway substrate 8 1. Introduction (Eps8) was initially identified as the substrate for the kinase activity of EGFR, improving the responsiveness of EGF, which Malignant tumours are uncontrolled cell proliferation diseases is involved in cell mitosis, differentiation and other physiological caused by oncogenes and ultimately lead to organ and body functions. Numerous studies over the last decade have demon- dysfunction (1). In recent decades, great progress has been strated that Eps8 is overexpressed in most ubiquitous malignant made in the study of genes and signalling pathways in tumours and subsequently binds with its receptor to activate tumorigenesis. Eps8 was identified by Fazioli et al in NIH-3T3 multiple signalling pathways. Eps8 not only participates in the murine fibroblasts via an approach that allows direct cloning regulation of malignant phenotypes, such as tumour proliferation, of intracellular substrates for receptor tyrosine kinases (RTKs) invasion, metastasis and drug resistance, but is also related to that was designed to study the EGFR signalling pathway. Eps8 the clinicopathological characteristics and prognosis of patients.
    [Show full text]
  • Noonan Syndrome and Related Disorders Sos1, Raf1, Kras & Shoc2 Gene Sequencing
    Molecular Diagnostic Laboratory 1600 Rockland Road, Wilmington, DE 19803 302.651.6775 email: [email protected] NOONAN SYNDROME AND RELATED DISORDERS SOS1, RAF1, KRAS & SHOC2 GENE SEQUENCING Noonan syndrome (OMIM 163950) is an autosomal dominant disorder due to mutations in several genes that are involved in the Ras-mitogen-activated protein kinase (RAS/MapK) pathway. Specifically, Noonan syndrome is caused by mutations in PTPN11* (OMIM 176876), SOS1 (OMIM 182530), RAF1 (OMIM 164760), and KRAS (OMIM 190070). Noonan syndrome is characterized by heart defects including hypertrophic cardiomyopathy and pulmonic valve stenosis, facial dysmorphology, short stature, chest wall deformities, and developmental delay. Noonan syndrome-like disorder with loose anagen hair (OMIM 607721) is a closely related disorder characterized by the above features as well as actively growing hair that is sparse, easy to pluck, thin, and slow-growing. This related disorder is due to mutations in SHOC2 (OMIM 602775), which is also involved in the RAS/MapK pathway. PTPN11* and RAF1 are also associated with LEOPARD syndrome (OMIM 151100). LEOPARD syndrome is an acronym for multiple lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonic valvular stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. LEOPARD syndrome is an autosomal dominant disorder, and can present much like Noonan syndrome with additional features. * Please note: We are no longer able to offer diagnostic testing for the PTPN11 gene due to patent restrictions enforced by U.S. Patent 7,335,469. Testing: Testing can be performed in tiers, moving to the next tier only if the preceding test is negative. Testing can also be performed concurrently or in any order requested.
    [Show full text]
  • Intersectin-1S Deficiency in Pulmonary Pathogenesis Niranjan Jeganathan1*, Dan Predescu2 and Sanda Predescu3
    Jeganathan et al. Respiratory Research (2017) 18:168 DOI 10.1186/s12931-017-0652-4 REVIEW Open Access Intersectin-1s deficiency in pulmonary pathogenesis Niranjan Jeganathan1*, Dan Predescu2 and Sanda Predescu3 Abstract Intersectin-1s (ITSN-1s), a multidomain adaptor protein, plays a vital role in endocytosis, cytoskeleton rearrangement and cell signaling. Recent studies have demonstrated that deficiency of ITSN-1s is a crucial early event in pulmonary pathogenesis. In lung cancer, ITSN-1s deficiency impairs Eps8 ubiquitination and favors Eps8-mSos1 interaction which activates Rac1 leading to enhanced lung cancer cell proliferation, migration and metastasis. Restoring ITSN-1s deficiency in lung cancer cells facilitates cytoskeleton changes favoring mesenchymal to epithelial transformation and impairs lung cancer progression. ITSN-1s deficiency in acute lung injury leads to impaired endocytosis which leads to ubiquitination and degradation of growth factor receptors such as Alk5. This deficiency is counterbalanced by microparticles which, via paracrine effects, transfer Alk5/TGFβRII complex to non-apoptotic cells. In the presence of ITSN-1s deficiency, Alk5-restored cells signal via Erk1/2 MAPK pathway leading to restoration and repair of lung architecture. In inflammatory conditions such as pulmonary artery hypertension, ITSN-1s full length protein is cleaved by granzyme B into EHITSN and SH3A-EITSN fragments. The EHITSN fragment leads to pulmonary cell proliferation via activation of p38 MAPK and Elk-1/c-Fos signaling. In vivo, ITSN-1s deficient mice transduced with EHITSN plasmid develop pulmonary vascular obliteration and plexiform lesions consistent with pathological findings seen in severe pulmonary arterial hypertension. These novel findings have significantly contributed to understanding the mechanisms and pathogenesis involved in pulmonary pathology.
    [Show full text]
  • PTPN11, SOS1, KRAS, and RAF1 Gene Analysis, and Genotype–Phenotype Correlation in Korean Patients with Noonan Syndrome
    J Hum Genet (2008) 53:999–1006 DOI 10.1007/s10038-008-0343-6 ORIGINAL ARTICLE PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype–phenotype correlation in Korean patients with Noonan syndrome Jung Min Ko Æ Jae-Min Kim Æ Gu-Hwan Kim Æ Han-Wook Yoo Received: 30 July 2008 / Accepted: 27 October 2008 / Published online: 20 November 2008 Ó The Japan Society of Human Genetics and Springer 2008 Abstract After 2006, germline mutations in the KRAS, KRAS (1.7%), and RAF1 (5.1%) genes. Three novel SOS1, and RAF1 genes were reported to cause Noonan mutations (T59A in PTPN11, K170E in SOS1, S259T in syndrome (NS), in addition to the PTPN11 gene, and now RAF1) were identified. The patients with PTPN11 muta- we can find the etiology of disease in approximately tions showed higher prevalences of patent ductus 60–70% of NS cases. The aim of this study was to assess arteriosus and thrombocytopenia. The patients with SOS1 the correlation between phenotype and genotype by mutations had a lower prevalence of delayed psychomotor molecular analysis of the PTPN11, SOS1, KRAS, and development. All patients with RAF1 mutations had RAF1 genes in 59 Korean patients with NS. We found hypertrophic cardiomyopathy. Typical facial features and disease-causing mutations in 30 (50.8%) patients, which auxological parameters were, on statistical analysis, not were located in the PTPN11 (27.1%), SOS1 (16.9%), significantly different between the groups. The molecular defects of NS are genetically heterogeneous and involve several genes other than PTPN11 related to the RAS- MAPK pathway. Electronic supplementary material The online version of this article (doi:10.1007/s10038-008-0343-6) contains supplementary material, which is available to authorized users.
    [Show full text]
  • Author's Personal Copy
    Author's personal copy Provided for non-commercial research and educational use only. Not for reproduction, distribution or commercial use. This article was originally published in the book Encyclopedia of Immunobiology, published by Elsevier, and the attached copy is provided by Elsevier for the author's benefit and for the benefit of the author's institution, for non-commercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who you know, and providing a copy to your institution's administrator. All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier’s permissions site at: http://www.elsevier.com/locate/permissionusematerial From Myers, D.R., Roose, J.P., 2016. Kinase and Phosphatase Effector Pathways in T Cells. In: Ratcliffe, M.J.H. (Editor in Chief), Encyclopedia of Immunobiology, Vol. 3, pp. 25–37. Oxford: Academic Press. Copyright © 2016 Elsevier Ltd. unless otherwise stated. All rights reserved. Academic Press Author's personal copy Kinase and Phosphatase Effector Pathways in T Cells Darienne R Myers and Jeroen P Roose, University of California, San Francisco (UCSF), San Francisco, CA, USA Ó 2016 Elsevier Ltd. All rights reserved. Abstract Multiple interconnected effector pathways mediate the activation of T cells following recognition of cognate antigen. These kinase and phosphatase pathways link proximal T cell receptor (TCR) signaling to changes in gene expression and cell physiology.
    [Show full text]
  • Fucoidan–Fucoxanthin Ameliorated Cardiac Function Via IRS1/GRB2/ SOS1, Gsk3β/CREB Pathways and Metabolic Pathways in Senescent Mice
    marine drugs Article Fucoidan–Fucoxanthin Ameliorated Cardiac Function via IRS1/GRB2/ SOS1, GSK3β/CREB Pathways and Metabolic Pathways in Senescent Mice Po-Ming Chang, Kuan-Lun Li and Yen-Chang Lin * Graduate Institute of Biotechnology, Chinese Culture University, Taipei 11114, Taiwan; [email protected] (P.-M.C.); [email protected] (K.-L.L.) * Correspondence: [email protected] or [email protected]; Tel.: +886-02-2861-0511 (ext. 31832); Fax: +886-02-2861-8266 Received: 3 November 2018; Accepted: 18 January 2019; Published: 21 January 2019 Abstract: The effects of low molecular weight fucoidan (LMWF) in combination with high-stability fucoxanthin (HSFUCO) on cardiac function and the metabolic pathways of aging mice (Mus musculus) were investigated. We demonstrated that LMWF and HSFUCO could improve cardiac function in aging mice. Aging mice were treated with LMWF and HSFUCO, either on their own or in combination, on 28 consecutive days. Electrocardiography and whole-cell patch-clamp were used to measure QT interval and action potential duration (APD) of the subjects. Cardiac tissue morphology, reactive oxygen species, and Western blot were also applied. Ultra-high-performance liquid chromatography–quadrupole time-of-flight (UPLC-QTOF) mass spectrometry was used for investigating metabolic alterations. The use of LMWF and HSFUCO resulted in improvements in both ventricular rhythms (QT and APD). Treatment with fucoidan and fucoxanthin reduced the expression levels of SOS1 and GRB2 while increasing GSK3β, CREB and IRS1 proteins expression in the aging process. Three main metabolic pathways, namely the TCA cycle, glycolysis, and steroid hormone biosynthesis, were highly enriched in the pathway enrichment analysis.
    [Show full text]
  • Amplification of Crklinduces Transformation and Epidermal
    Published OnlineFirst October 17, 2011; DOI: 10.1158/2159-8290.CD-11-0046 research article Cheung et al. ReseaRch aRticle amplification of CRKL induces transformation and epidermal Growth Factor receptor inhibitor resistance in human Non–small cell lung cancers Hiu Wing Cheung1,6,9, Jinyan Du2,9, Jesse S. Boehm9, Frank He2,9, Barbara A. Weir1,9, Xiaoxing Wang1,6,9, Mohit Butaney1,3, Lecia V. Sequist5,6, Biao Luo9, Jeffrey A. Engelman5,6, David E. Root9, Matthew Meyerson1,4,6,7,9, Todd R. Golub2,4,6,9, Pasi A. Jänne1,3,6, and William C. Hahn1,4,6,8,9 aBSTRACT We previously identified a region of recurrent amplification on chromosome 22q11.21 in a subset of primary lung adenocarcinomas. Here we show that CRKL, encoding for an adaptor protein, is amplified and overexpressed in non–small cell lung cancer (NSCLC) cells that harbor 22q11.21 amplifications. Overexpression of CRKL in immortal- ized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death. Overexpression of CRKL in epidermal growth factor receptor (EGFR)-mutant cells induces resistance to gefitinib by activating extracellular signal–regulated kinase and AKT signaling. We identified CRKL amplifica- tion in an EGFR inhibitor–treated lung adenocarcinoma that was not present before treatment. These observations demonstrate that CRKL overexpression induces cell transformation, creden- tial CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.
    [Show full text]
  • Small Molecule–Mediated Activation of RAS Elicits Biphasic Modulation of Phospho-ERK Levels That Are Regulated Through Negative Feedback on SOS1 Jennifer E
    Published OnlineFirst February 13, 2018; DOI: 10.1158/1535-7163.MCT-17-0666 Cancer Biology and Translational Studies Molecular Cancer Therapeutics Small Molecule–Mediated Activation of RAS Elicits Biphasic Modulation of Phospho-ERK Levels that Are Regulated through Negative Feedback on SOS1 Jennifer E. Howes, Denis T. Akan, Michael C. Burns, Olivia W. Rossanese, Alex G. Waterson, and Stephen W. Fesik Abstract Oncogenic mutation of RAS results in aberrant cellular inhibit the association between SOS1 and GRB2 and disrupt signaling and is responsible for more than 30% of all human SOS1 membrane localization. Consistent with this, we show tumors. Therefore, pharmacologic modulation of RAS has that wild-type SOS1 and GRB2 dissociated in a time-depen- attracted great interest as a therapeutic strategy. Our laboratory dentfashioninresponsetocompound treatment, and con- has recently discovered small molecules that activate Son of versely, this interaction was enhanced with the expression of Sevenless (SOS)–catalyzed nucleotide exchange on RAS and an S1178A SOS1 mutant. Furthermore, in cells expressing inhibit downstream signaling. Here, we describe how phar- either S1178A SOS1 or a constitutively membrane-bound macologically targeting SOS1 induced biphasic modulation of CAAX box tagged SOS1 mutant, we observed elevated RAS- RAS-GTP and ERK phosphorylation levels, which we observed GTP levels over time in response to compound, as compared in a variety of cell lines expressing different RAS-mutant iso- with the biphasic changes in RAS-GTP exhibited in cells forms. We show that compound treatment caused an increase expressing wild-type SOS1. These results suggest that small in phosphorylation at ERK consensus motifs on SOS1 that was molecule targeting of SOS1 can elicit a biphasic modulation of not observed with the expression of a non-phosphorylatable RAS-GTP and phospho-ERK levels through negative feedback S1178A SOS1 mutant or after pretreatment with an ERK on SOS1 that regulates the interaction between SOS1 and inhibitor.
    [Show full text]
  • A Mutation in the SOS1 Gene Causes Hereditary Gingival Fibromatosis Type 1 Thomas C
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Am. J. Hum. Genet. 70:943–954, 2002 A Mutation in the SOS1 Gene Causes Hereditary Gingival Fibromatosis Type 1 Thomas C. Hart,1,2 Yingze Zhang,1 Michael C. Gorry,1 P. Suzanne Hart,2 Margaret Cooper,1 Mary L. Marazita,1,2 Jared M. Marks,1 Jose R. Cortelli,3 and Debora Pallos3 1Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine, and 2Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh; and 3Department of Periodontics, School of Dentistry, University of Taubate, Taubate, Brazil Hereditary gingival fibromatosis (HGF) is a rare, autosomal dominant form of gingival overgrowth. Affected individuals have a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of the oral masticatory mucosa. Genetic loci for autosomal dominant forms of HGF have been localized to chromosome 2p21-p22 (HGF1) and chromosome 5q13-q22 (HGF2). To identify the gene responsible for HGF1, we extended genetic linkage studies to refine the chromosome 2p21-p22 candidate interval to ∼2.3 Mb. Development of an integrated physical and genetic map of the interval identified 16 genes. Sequencing of these genes, in affected and unaffected HGF1 family members, identified a mutation in the Son of sevenless–1 (SOS1) gene in affected individuals. In this report, we describe the genomic structure of the SOS1 gene and present evidence that insertion of a cytosine between nucleotides 126,142 and 126,143 in codon 1083 of the SOS1 gene is responsible for HGF1.
    [Show full text]
  • Elucidation of Protein-Protein Interactions Necessary for Maintenance of the BCR-ABL Signaling Complex
    bioRxiv preprint doi: https://doi.org/10.1101/684480; this version posted June 27, 2019. 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-ND 4.0 International license. Elucidation of protein-protein interactions necessary for maintenance of the BCR-ABL signaling complex Tomas Gregor1, Michaela Kunova Bosakova2,3, Alexandru Nita2, Sara P. Abraham2, Bohumil Fafilek2,3,5, Nicole H. Cernohorsky2, Jan Rynes1, Silvie Foldynova-Trantirkova1, Jiri Mayer4, Lukas Trantirek1,*, Pavel Krejci2,3,5,* 1Central European Institute of Technology, 2Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic 3International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic 4Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital, 62500 Brno, Czech Republic. 5Institute of Animal Physiology and Genetics of the CAS, 60200 Brno, Czech Republic *Correspondence to: [email protected], [email protected] Abstract Approximately 50% of chronic myeloid leukemia (CML) patients in deep remission experience a return of clinical CML after withdrawal of tyrosine kinase inhibitors (TKIs). This suggests signaling of inactive BCR-ABL, which allows for survival of cancer cells, leading to relapse. Understanding the dynamics of BCR-ABL signaling complex holds a key to the mechanism of BCR-ABL signaling. Here, we demonstrate
    [Show full text]
  • Understanding SOS (Son of Sevenless) Stéphane Pierre, Anne-Sophie Bats, Xavier Coumoul
    Understanding SOS (Son of Sevenless) Stéphane Pierre, Anne-Sophie Bats, Xavier Coumoul To cite this version: Stéphane Pierre, Anne-Sophie Bats, Xavier Coumoul. Understanding SOS (Son of Sevenless). Bio- chemical Pharmacology, Elsevier, 2011, 82 (9), pp.1049-1056. 10.1016/j.bcp.2011.07.072. hal- 02190799 HAL Id: hal-02190799 https://hal.archives-ouvertes.fr/hal-02190799 Submitted on 22 Jul 2019 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. *Manuscript Click here to view linked References Understanding SOS (Son of Sevenless). 1 1,2,‡ 1,2,3,‡ 1,2, † 2 Stéphane PIERRE , Anne-Sophie BATS , Xavier COUMOUL 3 4 5 1 6 INSERM UMR-S 747, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des 7 Saints Pères, 75006 Paris France 8 9 10 2 Université Paris Descartes, Centre universitaire des Saints-Pères, 45 rue des Saints Pères, 11 12 75006 Paris France 13 14 3 15 AP-HP, Hôpital Européen Georges Pompidou, Service de Chirurgie Gynécologique 16 17 Cancérologique, 75015 Paris France 18 19 ‡ These authors contributed equally to this work. 20 21 † 22 Address correspondence to: Xavier Coumoul, INSERM UMR-S 747, 45 rue des Saints-Pères 23 24 75006 Paris France; Phone: +33 1 42 86 33 59; Fax: +33 1 42 86 38 68; E-mail: 25 26 [email protected] 27 28 29 30 31 Key words: Son of Sevenless.
    [Show full text]