Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in GIST cells
Most gastrointestinal stromal tumors (GISTs) develop due to gain-of-function mutations in the tyrosine kinase, 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 KITs Golgi retention. In PKD2-inhibited cells, KIT migrates from the Golgi region to lysosomes and subsequently undergoes degradation. Importantly, delocalized KIT is unable to trigger downstream activation. In the Golgi area, KIT activates the PKD2-phosphatidylinositol 4-kinaseIII{beta} (PKD2-PI4KIII{beta}) pathway through phospholipase {gamma}2 (PLC{gamma}2) to generate a PI4P-rich membrane domain, where the AP1-GGA1 complex is aberrantly recruited. Disruption of any factors in this cascade results in KIT release from the Golgi region, indicating that these PKD2-related pathways are responsible for the Golgi retention of KIT. Our findings unveil the molecular mechanisms underlying KIT mislocalization and provide evidence for a new strategy for inhibition of oncogenic signaling.