Laboratory of Intracellular Traffic & Oncology, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Live Cell Super-Resolution Imaging Research Team, RIKEN Center for Advanced Photonics, Wako, Saitama 351-0198, Japan.
Cell Rep. 2023 Sep 26;42(9):113035. doi: 10.1016/j.celrep.2023.113035. Epub 2023 Aug 23.
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.
大多数胃肠道间质瘤（GIST）的发生是由于酪氨酸激酶基因 KIT 的功能获得性突变。我们最近表明，突变型 KIT 定位到高尔基体区域并引发不受控制的信号转导。然而，其高尔基体保留的分子机制尚不清楚。在这里，我们表明蛋白激酶 D2（PKD2）被突变体激活，导致 KIT 的高尔基体保留。在 PKD2 抑制的细胞中，KIT 从高尔基体区域迁移到溶酶体，随后发生降解。重要的是，去定位的 KIT 不能触发下游激活。在高尔基体/顺式高尔基体网络（TGN）中，KIT 通过磷脂酶 Cγ2（PLCγ2）激活 PKD2-磷脂酰肌醇 4-激酶 IIIβ（PKD2-PI4KIIIβ）途径，产生富含 PI4P 的膜结构域，其中异常募集了 AP1-GGA1 复合物。该级联中的任何因素的破坏都会导致 KIT 从高尔基体/TGN 中释放。我们的研究结果表明了 KIT 定位错误的分子机制，并为抑制致癌信号提供了策略的证据。
