Cell Reports (Jan 2017)

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

DOI
https://doi.org/10.1016/j.celrep.2016.12.056
Journal volume & issue
Vol. 18, no. 3
pp. 659 – 672

Abstract

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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.

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