Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells
Yuuki Obata,
Kazuo Kurokawa,
Takuro Tojima,
Miyuki Natsume,
Isamu Shiina,
Tsuyoshi Takahashi,
Ryo Abe,
Akihiko Nakano,
Toshirou Nishida
Affiliations
Yuuki Obata
Laboratory of Intracellular Traffic & Oncology, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Corresponding author
Kazuo Kurokawa
Live Cell Super-Resolution Imaging Research Team, RIKEN Center for Advanced Photonics, Wako, Saitama 351-0198, Japan
Takuro Tojima
Live Cell Super-Resolution Imaging Research Team, RIKEN Center for Advanced Photonics, Wako, Saitama 351-0198, Japan
Miyuki Natsume
Laboratory 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, Japan
Isamu Shiina
Department of Applied Chemistry, Tokyo University of Science, Shinjuku-ku, Tokyo 162-8601, Japan
Tsuyoshi Takahashi
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Ryo Abe
Tokyo University of Science, Noda, Chiba 278-8510, Japan
Akihiko Nakano
Live Cell Super-Resolution Imaging Research Team, RIKEN Center for Advanced Photonics, Wako, Saitama 351-0198, Japan
Toshirou Nishida
National 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, Japan
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.
