title: Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1.
abstract: Mutations in neurofibromin, a Ras GTPase-activating protein, lead to the tumor predisposition syndrome neurofibromatosis type 1. Here, we report that cells lacking neurofibromin exhibit enhanced glycolysis and decreased respiration in a Ras/ERK-dependent way. In the mitochondrial matrix of neurofibromin-deficient cells, a fraction of active ERK1/2 associates with succinate dehydrogenase (SDH) and TRAP1, a chaperone that promotes the accumulation of the oncometabolite succinate by inhibiting SDH. ERK1/2 enhances both formation of this multimeric complex and SDH inhibition. ERK1/2 kinase activity is favored by the interaction with TRAP1, and TRAP1 is, in turn, phosphorylated in an ERK1/2-dependent way. TRAP1 silencing or mutagenesis at the serine residues targeted by ERK1/2 abrogates tumorigenicity, a phenotype that is reverted by addition of a cell-permeable succinate analog. Our findings reveal that Ras/ERK signaling controls the metabolic changes orchestrated by TRAP1 that have a key role in tumor growth and are a promising target for anti-neoplastic strategies.
authors.affiliation: CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: Ionica
authors.initials: I
authors.lastname: Masgras
authors.affiliation: CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ciscato
authors.affiliation: Department of Molecular Medicine, University of Padova, 35131 Padova, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Brunati
authors.affiliation: Department of Molecular Medicine, University of Padova, 35131 Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tibaldi
authors.affiliation: Istituto Oncologico Veneto, IRCCS, 35128 Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
authors.affiliation: Istituto Oncologico Veneto, IRCCS, 35128 Padova, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Curtarello
authors.affiliation: Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova, 35128 Padova, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Chiara
authors.affiliation: CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cannino
authors.affiliation: Computational Biology Laboratory, Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
authors.forename: Elena
authors.initials: E
authors.lastname: Papaleo
authors.affiliation: Computational Biology Laboratory, Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
authors.forename: Matteo
authors.initials: M
authors.lastname: Lambrughi
authors.affiliation: CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Guzzo
authors.affiliation: Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova, 35128 Padova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gambalunga
authors.affiliation: Department of Medicine, University of Padova, 35128 Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pizzi
authors.affiliation: Department of Medicine, University of Padova, 35128 Padova, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Guzzardo
authors.affiliation: Department of Medicine, University of Padova, 35128 Padova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
authors.affiliation: Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova, 35128 Padova, Italy.
authors.forename: Stefania Edith
authors.initials: SE
authors.lastname: Vuljan
authors.affiliation: Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova, 35128 Padova, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Calabrese
authors.affiliation: CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.affiliation: CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy. Electronic address: andrea.rasola@unipd.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rasola
mesh_terms: D000818:Animals; D064113:CRISPR-Cas Systems / Q000235:genetics; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013386:Succinates / Q000737:chemistry / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D025542:Neurofibromin 1; D034741:RNA, Small Interfering; D013386:Succinates; C547760:TRAP-1 protein, mouse; D013385:Succinate Dehydrogenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D018631:ras Proteins
keywords: Ras/ERK signaling; TRAP1; bioenergetics; chaperones; mitochondria; neurofibromin; succinate dehydrogenase; tumor metabolism