Golgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependent
Abstract A constitutively active mutant of the receptor protein tyrosine kinase KIT is a major cause of gastrointestinal stromal tumours (GISTs). Recently, we discovered that, during biosynthetic transport, the KIT mutant (KITmut) is retained in the Golgi/trans-Golgi network (TGN), where it activate...
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Nature Portfolio
2025-08-01
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| Online Access: | https://doi.org/10.1038/s41598-025-14739-w |
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| author | Yuuki Obata Miyuki Natsume Isamu Shiina Tsuyoshi Takahashi Toshirou Nishida |
| author_facet | Yuuki Obata Miyuki Natsume Isamu Shiina Tsuyoshi Takahashi Toshirou Nishida |
| author_sort | Yuuki Obata |
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| description | Abstract A constitutively active mutant of the receptor protein tyrosine kinase KIT is a major cause of gastrointestinal stromal tumours (GISTs). Recently, we discovered that, during biosynthetic transport, the KIT mutant (KITmut) is retained in the Golgi/trans-Golgi network (TGN), where it activates downstream molecules. This retention is dependent on the phospholipase Cγ2–protein kinase D2–PI4 kinase IIIβ (PLCγ2–PKD2–PI4KIIIβ) pathway, which KITmut activates at the Golgi/TGN. The activated cascade aberrantly recruits GGA1 and the γ-adaptin subunit of AP1, resulting in KITmut retention in the Golgi/TGN. However, the precise mechanisms, including the mediators and effectors of the pathway, remain unclear. In humans, the phosphatidic acid-generating enzymes, phospholipase D1 (PLD1) and PLD2 are known downstream proteins of PKD. In the presence of the PLD inhibitor CAY10594, KITmut is released from the Golgi/TGN and subsequently degraded in lysosomes, leading to signal inactivation. Knockdown experiments indicated that PLD2 plays a role in KITmut retention. KITmut activates PLD2 through PKD2, but not PI4KIIIβ, for Golgi/TGN retention. PLD activity is required for the association of γ-adaptin with GGA1. Therefore, the KIT–PLCγ2–PKD2 pathway separately activates PLD2 and PI4KIIIβ to recruit γ-adaptin and GGA1. Collectively, these results suggest that KITmut retention is dependent on the activation of the PLCγ2–PKD2–PLD2 cascade in GIST cells. |
| format | Article |
| id | doaj-art-7dcdebfda1d3416e892b4323d982c909 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-7dcdebfda1d3416e892b4323d982c9092025-08-20T04:01:52ZengNature PortfolioScientific Reports2045-23222025-08-0115111310.1038/s41598-025-14739-wGolgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependentYuuki Obata0Miyuki Natsume1Isamu Shiina2Tsuyoshi Takahashi3Toshirou Nishida4Laboratory of Intracellular Traffic & Oncology, National Cancer Center Research InstituteLaboratory of Intracellular Traffic & Oncology, National Cancer Center Research InstituteDepartment of Applied Chemistry, Faculty of Science, Tokyo University of ScienceDepartment of Gastroenterological Surgery, Graduate School of Medicine, Osaka UniversityNational Cancer Center HospitalAbstract A constitutively active mutant of the receptor protein tyrosine kinase KIT is a major cause of gastrointestinal stromal tumours (GISTs). Recently, we discovered that, during biosynthetic transport, the KIT mutant (KITmut) is retained in the Golgi/trans-Golgi network (TGN), where it activates downstream molecules. This retention is dependent on the phospholipase Cγ2–protein kinase D2–PI4 kinase IIIβ (PLCγ2–PKD2–PI4KIIIβ) pathway, which KITmut activates at the Golgi/TGN. The activated cascade aberrantly recruits GGA1 and the γ-adaptin subunit of AP1, resulting in KITmut retention in the Golgi/TGN. However, the precise mechanisms, including the mediators and effectors of the pathway, remain unclear. In humans, the phosphatidic acid-generating enzymes, phospholipase D1 (PLD1) and PLD2 are known downstream proteins of PKD. In the presence of the PLD inhibitor CAY10594, KITmut is released from the Golgi/TGN and subsequently degraded in lysosomes, leading to signal inactivation. Knockdown experiments indicated that PLD2 plays a role in KITmut retention. KITmut activates PLD2 through PKD2, but not PI4KIIIβ, for Golgi/TGN retention. PLD activity is required for the association of γ-adaptin with GGA1. Therefore, the KIT–PLCγ2–PKD2 pathway separately activates PLD2 and PI4KIIIβ to recruit γ-adaptin and GGA1. Collectively, these results suggest that KITmut retention is dependent on the activation of the PLCγ2–PKD2–PLD2 cascade in GIST cells.https://doi.org/10.1038/s41598-025-14739-wRTKKITGISTGolgi/TGNPKDPLD |
| spellingShingle | Yuuki Obata Miyuki Natsume Isamu Shiina Tsuyoshi Takahashi Toshirou Nishida Golgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependent Scientific Reports RTK KIT GIST Golgi/TGN PKD PLD |
| title | Golgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependent |
| title_full | Golgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependent |
| title_fullStr | Golgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependent |
| title_full_unstemmed | Golgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependent |
| title_short | Golgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependent |
| title_sort | golgi retention of kit in gastrointestinal stromal tumour cells is phospholipase d activity dependent |
| topic | RTK KIT GIST Golgi/TGN PKD PLD |
| url | https://doi.org/10.1038/s41598-025-14739-w |
| work_keys_str_mv | AT yuukiobata golgiretentionofkitingastrointestinalstromaltumourcellsisphospholipasedactivitydependent AT miyukinatsume golgiretentionofkitingastrointestinalstromaltumourcellsisphospholipasedactivitydependent AT isamushiina golgiretentionofkitingastrointestinalstromaltumourcellsisphospholipasedactivitydependent AT tsuyoshitakahashi golgiretentionofkitingastrointestinalstromaltumourcellsisphospholipasedactivitydependent AT toshirounishida golgiretentionofkitingastrointestinalstromaltumourcellsisphospholipasedactivitydependent |