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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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-14739-w |
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| Summary: | 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. |
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| ISSN: | 2045-2322 |