Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth

Mol Cell. 2015 Feb 5;57(3):537-51. doi: 10.1016/j.molcel.2015.01.002.

Abstract

Ras is mutated in up to 30% of cancers, including 90% of pancreatic ductal adenocarcinomas, causing it to be constitutively GTP-bound, and leading to activation of downstream effectors that promote a tumorigenic phenotype. As targeting Ras directly is difficult, there is a significant effort to understand the downstream biological processes that underlie its protumorigenic activity. Here, we show that expression of oncogenic Ras or direct activation of the MAPK pathway leads to increased mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits tumor growth. This fission is driven by Erk2-mediated phosphorylation of Drp1 on Serine 616, and both this phosphorylation and mitochondrial fragmentation are increased in human pancreatic cancer. Finally, this phosphorylation is required for Ras-associated mitochondrial fission, and its inhibition is sufficient to block xenograft growth. Collectively, these data suggest mitochondrial fission may be a target for treating MAPK-driven malignancies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Dynamins
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Nude
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Mitochondrial Dynamics* / drug effects
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Neoplasms, Experimental / metabolism
  • Pancreatic Neoplasms / metabolism*
  • Phosphorylation
  • Serine / metabolism
  • ras Proteins / metabolism

Substances

  • Benzamides
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • PD 0325901
  • Serine
  • Diphenylamine
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • GTP Phosphohydrolases
  • ras Proteins
  • DNM1L protein, human
  • Dynamins