胃肠道间质瘤（GISTs）大多数由酪氨酸激酶基因KIT的增益功能突变引发。我们最近发现突变的KIT会错位至高尔基区域并启动不受控制的信号传递。然而，该错位的高尔基滞留的分子机制尚不清楚。在这里，我们展示突变体激活了蛋白激酶D2（PKD2），导致KIT在高尔基滞留。在PKD2受抑制的细胞中，KIT从高尔基区域迁移至溶酶体并被降解。重要的是，错位的KIT无法触发下游激活。在高尔基/转高尔基网络（TGN）中，KIT通过磷脂酶Cγ2（PLCγ2）激活PKD2-磷酸肌醇4激酶IIIβ（PKD2-PI4KIIIβ）途径产生富含PI4P的膜结构域，在其中异常招募AP1-GGA1复合物。对该级联中的任何因子的干扰都会导致KIT从高尔基/TGN中释放。我们的发现揭示了KIT错位的分子机制，并为抑制致癌信号传递提供了策略的证据。版权所有 © 2023 作者。由Elsevier Inc.发表。版权所有。

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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.