PP6 Disruption Synergizes with Oncogenic Ras to Promote JNK-Dependent Tumor Growth and Invasion

Publication date: 27 June 2017
Source:Cell Reports, Volume 19, Issue 13
Author(s): Xianjue Ma, Jin-Yu Lu, Yongli Dong, Daming Li, Juan N. Malagon, Tian Xu
RAS genes are frequently mutated in cancers, yet an effective treatment has not been developed, partly because of an incomplete understanding of signaling within Ras-related tumors. To address this, we performed a genetic screen in Drosophila, aiming to find mutations that cooperate with oncogenic Ras (Ras^V12) to induce tumor overgrowth and invasion. We identified fiery mountain (fmt), a regulatory subunit of the protein phosphatase 6 (PP6) complex, as a tumor suppressor that synergizes with Ras^V12 to drive c-Jun N-terminal kinase (JNK)-dependent tumor growth and invasiveness. We show that Fmt negatively regulates JNK upstream of dTAK1. We further demonstrate that disruption of PpV, the catalytic subunit of PP6, mimics fmt loss-of-function-induced tumorigenesis. Finally, Fmt synergizes with PpV to inhibit JNK-dependent tumor progression. Our data here further highlight the power of Drosophila as a model system to unravel molecular mechanisms that may be relevant to human cancer biology.

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Teaser

Ma et al. perform an ethyl methanesulphonate (EMS) screen in Drosophila and identify CG10289 (Fmt), a regulatory subunit of the PP6 complex, as a tumor suppressor. They find that loss of Fmt or PpV, the catalytic subunit of PP6, synergizes with Ras^V12 to drive JNK-dependent tumor growth upstream of dTAK1.


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