Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1
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 neurofibr...
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doaj-5ef12b229fed44ec8de2df96396d13522020-11-25T02:21:15ZengElsevierCell Reports2211-12472017-01-0118365967210.1016/j.celrep.2016.12.056Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1Ionica Masgras0Francesco Ciscato1Anna Maria Brunati2Elena Tibaldi3Stefano Indraccolo4Matteo Curtarello5Federica Chiara6Giuseppe Cannino7Elena Papaleo8Matteo Lambrughi9Giulia Guzzo10Alberto Gambalunga11Marco Pizzi12Vincenza Guzzardo13Massimo Rugge14Stefania Edith Vuljan15Fiorella Calabrese16Paolo Bernardi17Andrea Rasola18CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, ItalyCNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, ItalyDepartment of Molecular Medicine, University of Padova, 35131 Padova, ItalyDepartment of Molecular Medicine, University of Padova, 35131 Padova, ItalyIstituto Oncologico Veneto, IRCCS, 35128 Padova, ItalyIstituto Oncologico Veneto, IRCCS, 35128 Padova, ItalyDepartment of Cardiac, Thoracic, and Vascular Sciences, University of Padova, 35128 Padova, ItalyCNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, ItalyComputational Biology Laboratory, Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, 2100 Copenhagen, DenmarkComputational Biology Laboratory, Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, 2100 Copenhagen, DenmarkCNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, ItalyDepartment of Cardiac, Thoracic, and Vascular Sciences, University of Padova, 35128 Padova, ItalyDepartment of Medicine, University of Padova, 35128 Padova, ItalyDepartment of Medicine, University of Padova, 35128 Padova, ItalyDepartment of Medicine, University of Padova, 35128 Padova, ItalyDepartment of Cardiac, Thoracic, and Vascular Sciences, University of Padova, 35128 Padova, ItalyDepartment of Cardiac, Thoracic, and Vascular Sciences, University of Padova, 35128 Padova, ItalyCNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, ItalyCNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35131 Padova, ItalyMutations 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.http://www.sciencedirect.com/science/article/pii/S2211124716317636Ras/ERK signalingTRAP1succinate dehydrogenaseneurofibromintumor metabolismmitochondriachaperonesbioenergetics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ionica Masgras Francesco Ciscato Anna Maria Brunati Elena Tibaldi Stefano Indraccolo Matteo Curtarello Federica Chiara Giuseppe Cannino Elena Papaleo Matteo Lambrughi Giulia Guzzo Alberto Gambalunga Marco Pizzi Vincenza Guzzardo Massimo Rugge Stefania Edith Vuljan Fiorella Calabrese Paolo Bernardi Andrea Rasola |
spellingShingle |
Ionica Masgras Francesco Ciscato Anna Maria Brunati Elena Tibaldi Stefano Indraccolo Matteo Curtarello Federica Chiara Giuseppe Cannino Elena Papaleo Matteo Lambrughi Giulia Guzzo Alberto Gambalunga Marco Pizzi Vincenza Guzzardo Massimo Rugge Stefania Edith Vuljan Fiorella Calabrese Paolo Bernardi Andrea Rasola Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1 Cell Reports Ras/ERK signaling TRAP1 succinate dehydrogenase neurofibromin tumor metabolism mitochondria chaperones bioenergetics |
author_facet |
Ionica Masgras Francesco Ciscato Anna Maria Brunati Elena Tibaldi Stefano Indraccolo Matteo Curtarello Federica Chiara Giuseppe Cannino Elena Papaleo Matteo Lambrughi Giulia Guzzo Alberto Gambalunga Marco Pizzi Vincenza Guzzardo Massimo Rugge Stefania Edith Vuljan Fiorella Calabrese Paolo Bernardi Andrea Rasola |
author_sort |
Ionica Masgras |
title |
Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1 |
title_short |
Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1 |
title_full |
Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1 |
title_fullStr |
Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1 |
title_full_unstemmed |
Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1 |
title_sort |
absence of neurofibromin induces an oncogenic metabolic switch via mitochondrial erk-mediated phosphorylation of the chaperone trap1 |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2017-01-01 |
description |
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. |
topic |
Ras/ERK signaling TRAP1 succinate dehydrogenase neurofibromin tumor metabolism mitochondria chaperones bioenergetics |
url |
http://www.sciencedirect.com/science/article/pii/S2211124716317636 |
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