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

Publication ,  Journal Article
Kashatus, JA; Nascimento, A; Myers, LJ; Sher, A; Byrne, FL; Hoehn, KL; Counter, CM; Kashatus, DF
Published in: Mol Cell
February 5, 2015

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.

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Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

February 5, 2015

Volume

57

Issue

3

Start / End Page

537 / 551

Location

United States

Related Subject Headings

  • ras Proteins
  • Serine
  • Phosphorylation
  • Pancreatic Neoplasms
  • Neoplasms, Experimental
  • Mitogen-Activated Protein Kinase 1
  • Mitochondrial Proteins
  • Mitochondrial Dynamics
  • Microtubule-Associated Proteins
  • Mice, Nude
 

Citation

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Kashatus, J. A., Nascimento, A., Myers, L. J., Sher, A., Byrne, F. L., Hoehn, K. L., … Kashatus, D. F. (2015). Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell, 57(3), 537–551. https://doi.org/10.1016/j.molcel.2015.01.002
Kashatus, Jennifer A., Aldo Nascimento, Lindsey J. Myers, Annie Sher, Frances L. Byrne, Kyle L. Hoehn, Christopher M. Counter, and David F. Kashatus. “Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth.Mol Cell 57, no. 3 (February 5, 2015): 537–51. https://doi.org/10.1016/j.molcel.2015.01.002.
Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL, et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell. 2015 Feb 5;57(3):537–51.
Kashatus, Jennifer A., et al. “Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth.Mol Cell, vol. 57, no. 3, Feb. 2015, pp. 537–51. Pubmed, doi:10.1016/j.molcel.2015.01.002.
Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL, Counter CM, Kashatus DF. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell. 2015 Feb 5;57(3):537–551.
Journal cover image

Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

February 5, 2015

Volume

57

Issue

3

Start / End Page

537 / 551

Location

United States

Related Subject Headings

  • ras Proteins
  • Serine
  • Phosphorylation
  • Pancreatic Neoplasms
  • Neoplasms, Experimental
  • Mitogen-Activated Protein Kinase 1
  • Mitochondrial Proteins
  • Mitochondrial Dynamics
  • Microtubule-Associated Proteins
  • Mice, Nude