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Golgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependent.

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Title: Golgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependent.
Authors: Obata Y; Laboratory of Intracellular Traffic & Oncology, National Cancer Center Research Institute, Tsukiji, 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. yuobata@ncc.go.jp., Natsume M; Laboratory of Intracellular Traffic & Oncology, National Cancer Center Research Institute, Tsukiji, 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.; Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Shinjuku-ku, Tokyo, 162-8601, Japan., Shiina I; Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Shinjuku-ku, Tokyo, 162-8601, Japan., Takahashi T; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, 565-0871, Osaka, Japan., Nishida T; National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Source: Scientific reports [Sci Rep] 2025 Aug 06; Vol. 15 (1), pp. 28778. Date of Electronic Publication: 2025 Aug 06.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
Imprint Name(s): Original Publication: London : Nature Publishing Group, copyright 2011-
MeSH Terms: Phospholipase D*/metabolism , Phospholipase D*/genetics , Phospholipase D*/antagonists & inhibitors , Gastrointestinal Stromal Tumors*/metabolism , Gastrointestinal Stromal Tumors*/pathology , Gastrointestinal Stromal Tumors*/genetics , Golgi Apparatus*/metabolism , Proto-Oncogene Proteins c-kit*/metabolism , Proto-Oncogene Proteins c-kit*/genetics , Gastrointestinal Neoplasms*/metabolism, Phospholipase C gamma/metabolism ; trans-Golgi Network/metabolism ; Humans ; Cell Line, Tumor ; Signal Transduction ; Mutation
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.
(© 2025. The Author(s).)
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
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Contributed Indexing: Keywords: GIST; Golgi/TGN; KIT; PKD; PLD; RTK
Substance Nomenclature: EC 3.1.4.4 (Phospholipase D)
EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
EC 3.1.4.3 (Phospholipase C gamma)
EC 2.7.10.1 (KIT protein, human)
EC 3.1.4.4 (phospholipase D1)
EC 3.1.4.- (phospholipase D2)
Entry Date(s): Date Created: 20250806 Date Completed: 20250806 Latest Revision: 20250809
Update Code: 20260130
PubMed Central ID: PMC12328827
DOI: 10.1038/s41598-025-14739-w
PMID: 40770227
Database: MEDLINE
Description
ISSN:2045-2322
DOI:10.1038/s41598-025-14739-w