Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells
Summary: Most gastrointestinal stromal tumors (GISTs) develop due to gain-of-function mutations in the tyrosine kinase gene, KIT. We recently showed that mutant KIT mislocalizes to the Golgi area and initiates uncontrolled signaling. However, the molecular mechanisms underlying its Golgi retention r...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472301046X |
| _version_ | 1797737974551543808 |
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| author | Yuuki Obata Kazuo Kurokawa Takuro Tojima Miyuki Natsume Isamu Shiina Tsuyoshi Takahashi Ryo Abe Akihiko Nakano Toshirou Nishida |
| author_facet | Yuuki Obata Kazuo Kurokawa Takuro Tojima Miyuki Natsume Isamu Shiina Tsuyoshi Takahashi Ryo Abe Akihiko Nakano Toshirou Nishida |
| author_sort | Yuuki Obata |
| collection | DOAJ |
| description | Summary: Most gastrointestinal stromal tumors (GISTs) develop due to gain-of-function mutations in the tyrosine kinase gene, KIT. We recently showed that mutant KIT mislocalizes to the Golgi area and initiates uncontrolled signaling. However, the molecular mechanisms underlying its Golgi retention remain unknown. Here, we show 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 region to lysosomes and subsequently undergoes degradation. Importantly, delocalized KIT cannot trigger downstream activation. In the Golgi/trans-Golgi network (TGN), KIT activates the PKD2-phosphatidylinositol 4-kinase IIIβ (PKD2-PI4KIIIβ) pathway through phospholipase Cγ2 (PLCγ2) to generate a PI4P-rich membrane domain, where the AP1-GGA1 complex is aberrantly recruited. Disruption of any factors in this cascade results in the release of KIT from the Golgi/TGN. Our findings show the molecular mechanisms underlying KIT mislocalization and provide evidence for a strategy for inhibition of oncogenic signaling. |
| first_indexed | 2024-03-12T13:36:13Z |
| format | Article |
| id | doaj.art-42d0f84a4a38424993fb2a24722927da |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T13:36:13Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-42d0f84a4a38424993fb2a24722927da2023-08-24T04:35:03ZengElsevierCell Reports2211-12472023-09-01429113035Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cellsYuuki Obata0Kazuo Kurokawa1Takuro Tojima2Miyuki Natsume3Isamu Shiina4Tsuyoshi Takahashi5Ryo Abe6Akihiko Nakano7Toshirou Nishida8Laboratory of Intracellular Traffic & Oncology, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Corresponding authorLive Cell Super-Resolution Imaging Research Team, RIKEN Center for Advanced Photonics, Wako, Saitama 351-0198, JapanLive Cell Super-Resolution Imaging Research Team, RIKEN Center for Advanced Photonics, Wako, Saitama 351-0198, JapanLaboratory of Intracellular Traffic & Oncology, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Applied Chemistry, Tokyo University of Science, Shinjuku-ku, Tokyo 162-8601, JapanDepartment of Applied Chemistry, Tokyo University of Science, Shinjuku-ku, Tokyo 162-8601, JapanDepartment of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, JapanTokyo University of Science, Noda, Chiba 278-8510, JapanLive Cell Super-Resolution Imaging Research Team, RIKEN Center for Advanced Photonics, Wako, Saitama 351-0198, JapanNational Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, JapanSummary: Most gastrointestinal stromal tumors (GISTs) develop due to gain-of-function mutations in the tyrosine kinase gene, KIT. We recently showed that mutant KIT mislocalizes to the Golgi area and initiates uncontrolled signaling. However, the molecular mechanisms underlying its Golgi retention remain unknown. Here, we show 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 region to lysosomes and subsequently undergoes degradation. Importantly, delocalized KIT cannot trigger downstream activation. In the Golgi/trans-Golgi network (TGN), KIT activates the PKD2-phosphatidylinositol 4-kinase IIIβ (PKD2-PI4KIIIβ) pathway through phospholipase Cγ2 (PLCγ2) to generate a PI4P-rich membrane domain, where the AP1-GGA1 complex is aberrantly recruited. Disruption of any factors in this cascade results in the release of KIT from the Golgi/TGN. Our findings show the molecular mechanisms underlying KIT mislocalization and provide evidence for a strategy for inhibition of oncogenic signaling.http://www.sciencedirect.com/science/article/pii/S221112472301046XCP: CancerCP: Molecular biology |
| spellingShingle | Yuuki Obata Kazuo Kurokawa Takuro Tojima Miyuki Natsume Isamu Shiina Tsuyoshi Takahashi Ryo Abe Akihiko Nakano Toshirou Nishida Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells Cell Reports CP: Cancer CP: Molecular biology |
| title | Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells |
| title_full | Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells |
| title_fullStr | Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells |
| title_full_unstemmed | Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells |
| title_short | Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells |
| title_sort | golgi retention and oncogenic kit signaling via plcγ2 pkd2 pi4kiiiβ activation in gastrointestinal stromal tumor cells |
| topic | CP: Cancer CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S221112472301046X |
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