Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells

Cell Rep. 2023 Sep 26;42(9):113035. doi: 10.1016/j.celrep.2023.113035. Epub 2023 Aug 23.

Abstract

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.

Keywords: AP1; CP: Cancer; CP: Molecular biology; GGA1; GIST; Golgi/TGN; KIT; PI4KIIIβ; PKD2; PLCγ2; mislocalization; receptor tyrosine kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gastrointestinal Stromal Tumors* / genetics
  • Gastrointestinal Stromal Tumors* / metabolism
  • Gastrointestinal Stromal Tumors* / pathology
  • Golgi Apparatus / metabolism
  • Humans
  • Phospholipase C gamma / metabolism
  • Protein Kinase D2
  • Proto-Oncogene Proteins c-kit / metabolism
  • trans-Golgi Network / metabolism

Substances

  • Protein Kinase D2
  • Phospholipase C gamma
  • Proto-Oncogene Proteins c-kit