Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth.
Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth.
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DOI：
10.1016/j.molcel.2015.01.002
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发表时间：
2015-02-05
期刊：
影响因子：
16
通讯作者：
Kashatus, David F.
中科院分区：
文献类型：
--
作者：
Kashatus, Jennifer A.;Nascimento, Aldo;Myers, Lindsey J.;Sher, Annie;Byrne, Frances L.;Hoehn, Kyle L.;Counter, Christopher M.;Kashatus, David F.
Ras 在高达 30% 的癌症中发生突变，包括 90% 的胰腺导管腺癌，导致其与 GTP 结合，并导致下游效应器激活，从而促进致瘤表型。由于直接靶向 Ras 很困难，因此需要付出巨大努力来了解其促肿瘤活性的下游生物过程。在这里，我们发现致癌 Ras 的表达或 MAPK 通路的直接激活会导致线粒体碎片增加，并且通过敲低线粒体裂变介导的 GTPase Drp1 来阻断这种表型，从而抑制肿瘤生长。这种裂变是由 Erk2 介导的 Drp1 在丝氨酸 616 上的磷酸化驱动的，并且这种磷酸化和线粒体断裂在人类胰腺癌中都会增加。最后，这种磷酸化是 Ras 相关线粒体裂变所必需的，其抑制足以阻止异种移植物生长。总的来说，这些数据表明线粒体裂变可能是治疗 MAPK 驱动的恶性肿瘤的目标。
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.
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