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

By Jennifer A. Kashatus, Aldo Nascimento, Lindsey J. Myers, A. Sher, F. Byrne, Kyle L. Hoehn, C. Counter, David F. Kashatus. Molecules and Cells, 2015

644 citations recorded by the source corpus.

Summary 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 pro-tumorigenic 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/02da44130c6840558c1a015bae8fb5c8529814f0

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In Cancer Research

1. L. Galluzzi
2. Guido Kroemer
3. J. B. Pedro
4. P. Porporato
5. N. Filigheddu

In Molecular Biology

1. L. Galluzzi
2. Guido Kroemer
3. Prashant Mishra
4. J. B. Pedro
5. P. Porporato
6. N. Filigheddu
7. D. C. Chan
8. Douglas R. Green

Citations in the corpus

• Metabolic regulation of mitochondrial dynamics (2016, background): “Drp1 phosphorylation at S616 has also been implicated in tumorigenesis by oncogenic Ras (Fig. 3; Kashatus et al., 2015; Serasinghe et al., 2015).”
• Mitochondrial metabolism and cancer (2017, background): “, MYC, KRAS) drive malignant transformation as they increase the resistance of the mitochondrial pool to MOMP or MPT, in some cases via a mechanism that alters mitochondrial dynamics [55-57].”