Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)659-672
Number of pages14
JournalCell Reports
Volume18
Issue number3
DOIs
Publication statusPublished - Jan 17 2017

Keywords

  • bioenergetics
  • chaperones
  • mitochondria
  • neurofibromin
  • Ras/ERK signaling
  • succinate dehydrogenase
  • TRAP1
  • tumor metabolism

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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