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 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.
Mesh Terms:
Animals, CRISPR-Cas Systems, Cell Line, HSP90 Heat-Shock Proteins, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, MAP Kinase Kinase 1, Mice, Mitochondria, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Molecular Dynamics Simulation, Neurofibromin 1, Phosphorylation, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Signal Transduction, Succinate Dehydrogenase, Succinates, ras Proteins
Cell Rep
Date: Dec. 17, 2016
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