2023 Fiscal Year Final Research Report
Molecular mechanism of Golgi retention of RTK mutant and establishment of a new strategy for inhibition of tyrosine phosphorylation signaling
| Project/Area Number |
21K07163
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | National Cancer Center Japan |
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Principal Investigator |
Obata Yuuki 国立研究開発法人国立がん研究センター, 研究所, ユニット長 (20609408)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | 受容体型チロシンキナーゼ / ゴルジ/TGN / KIT / 局在異常 / 消化管間質腫瘍 (GIST) / PKD2 / PI4KB |
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| Outline of Final Research Achievements |
Most gastrointestinal stromal tumors (GISTs) develop due to gain-of-function mutations in the tyrosine kinase, KIT. We recently showed that mutant KIT mislocalizes to the Golgi/trans-Golgi network (TGN) and initiates oncogenic signaling. However, the molecular mechanisms underlying its Golgi retention remain unknown. In this study, we found that protein kinase D2 (PKD2) is activated by the mutant, which causes Golgi retention of KIT. In PKD2-inhibited cells, KIT migrates from the Golgi/TGN to lysosomes and subsequently undergoes degradation. Importantly, delocalized KIT cannot trigger downstream activation. In the Golgi/TGN, KIT activates the PKD2-PI4KB pathway to generate a PI4P-rich membrane domain, where the AP1 is aberrantly recruited. Disruption of any factors in this cascade results in the release of KIT from the Golgi/TGN. Our findings unveil the molecular mechanisms underlying KIT mislocalization and provide evidence for a new strategy for inhibition of oncogenic signaling.
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| Free Research Field |
腫瘍生物学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、分子標的薬感受性のKITのみではなく、耐性型KIT変異体も、PKD2依存的にゴルジ領域に停留することを示唆するデータを得ている。PKDインヒビターが、ゴルジ停留の解除を介し、標的薬抵抗型KIT変異体のシグナル発信を抑制することが示唆され、新機序阻害法の開発の一助となるものと考えられる。一方、他のがん種の変異受容体チロシンキナーゼのゴルジ停留は、PKD2活性化では説明できず、それぞれのがんにおける分子メカニズムの解析の重要性も明らかになった。新たなシグナル阻害戦術を見出した点と、他がん種での丁寧な解析の必要性を喚起した点で、本研究の意義は大きいと考えられる。
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