title: Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth.
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.
authors: Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors: Jennifer A
authors: JA
authors: Kashatus
authors: Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors: Aldo
authors: A
authors: Nascimento
authors: Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors: Lindsey J
authors: LJ
authors: Myers
authors: Department of Pharmacology and Cancer Biology, Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Annie
authors: A
authors: Sher
authors: Department of Pharmacology, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors: Frances L
authors: FL
authors: Byrne
authors: Department of Pharmacology, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors: Kyle L
authors: KL
authors: Hoehn
authors: Department of Pharmacology and Cancer Biology, Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Christopher M
authors: CM
authors: Counter
authors: Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA. Electronic address: kashatus@virginia.edu.
authors: David F
authors: DF
authors: Kashatus
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D001549:Benzamides; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D012694:Serine; C506614:mirdametinib; D004159:Diphenylamine; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D020558:GTP Phosphohydrolases; D018631:ras Proteins; C110768:DNM1L protein, human; D034281:Dynamins