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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Kashatus, JA; Nascimento, A; Myers, LJ; Sher, A; Byrne, FL; Hoehn, KL; Counter, CM; Kashatus, DF

Published Date

  • February 2015

Published In

Volume / Issue

  • 57 / 3

Start / End Page

  • 537 - 551

PubMed ID

  • 25658205

Pubmed Central ID

  • 25658205

Electronic International Standard Serial Number (EISSN)

  • 1097-4164

International Standard Serial Number (ISSN)

  • 1097-2765

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2015.01.002

Language

  • eng