| Project/Area Number |
16K18427
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Tumor biology
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| Research Institution | Tokyo University of Science |
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Principal Investigator |
Yuuki Obata 東京理科大学, 研究推進機構生命医科学研究所, 講師 (20609408)
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| Project Period (FY) |
2016-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 消化管間質細胞腫 / Kitチロシンキナーゼ / ゴルジ体 / PI3K-Akt経路 / STAT5 / Mek-Erk経路 / イマチニブ / GIST / c-Kit / PI3K / Akt / マスト細胞腫 / ゴルジ / 細胞内輸送 / PI3K-Akt / STATs |
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| Outline of Final Research Achievements |
GISTs are caused by activating mutations in the Kit tyrosine kinase. Most primary GIST patients respond to the Kit inhibitor imatinib, but this drug often becomes ineffective because of secondary mutations in the Kit kinase domain. The characteristic intracellular accumulation of imatinib-sensitive and -resistant Kit is well documented, but its relationship to oncogenic signaling remains unknown. Here, we show that in cancer tissue from primary GIST patients as well as in cell lines, mutant Kit(Kit(mut)) accumulates on the Golgi. In imatinib-resistant GIST with a secondary Kit mutation, Kit localizes on the Golgi. Furthermore, Kit(mut) on the Golgi signals and activates Akt and STAT5. Blocking the biosynthetic transport of Kit(mut) to the Golgi from the ER inhibits oncogenic signaling. These results suggest that the Golgi serves as a platform for oncogenic Kit signaling. Our study may offer a new strategy for treating imatinib-resistant GISTs.
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