title: Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling.
abstract: AIRAPL (arsenite-inducible RNA-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but its biological function in mammals is unknown. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease found in AIRAPL-deficient mice as well as that in mice carrying the Jak2(V617F) mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, AIRAPL expression is widely abrogated in human myeloproliferative disorders. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and they unveil novel therapeutic targets for these frequent hematological neoplasias.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Osorio
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Soria-Valles
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Olaya
authors.initials: O
authors.lastname: Santiago-Fernández
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.|Servicio de Hematología, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Bernal
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.|Instituto de Investigación Sanitaria, Hospital 12 de Octubre (i+12), Madrid, Spain.|Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Mittelbrunn
authors.affiliation: Servicio de Hematología, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Colado
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Rodríguez
authors.affiliation: Laboratory of Cardiovascular Proteomics, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonzon-Kulichenko
authors.affiliation: Laboratory of Cardiovascular Proteomics, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Vázquez
authors.affiliation: Area of Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.|Caenorhabditis elegans Facility, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Porta-de-la-Riva
authors.affiliation: Area of Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Cerón
authors.affiliation: Área de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fueyo
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.|Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: José M P
authors.initials: JM
authors.lastname: Freije
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D064113:CRISPR-Cas Systems; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D040901:Proteomics; D057165:Proteostasis Deficiencies; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics; D015398:Signal Transduction; D054875:Ubiquitination; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D008840:Microfilament Proteins; D016601:RNA-Binding Proteins; C544166:ZFAND2B protein, human; C000607774:Zfand2b protein, mouse; C423987:unc-78 protein, C elegans; D007334:Insulin-Like Growth Factor I; C107483:DAF-2 protein, C elegans; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D046988:Proteasome Endopeptidase Complex