Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in GIST cells.
Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in GIST cells.
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GIST 细胞中通过 PLCγ2-PKD2-PI4KIIIβ 激活高尔基体滞留和致癌 KIT 信号传导。
DOI：
10.1101/2022.12.19.520889
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Nakano A & Nishida T
中科院分区：
文献类型：
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作者：
Obata Y;Kurokawa K;Tojima T;Natsume M;Shiina I;Takahashi T;Abe R;Nakano A & Nishida T
大多数胃肠道间质瘤（GIST）的发展是由于酪氨酸激酶（KIT）的功能获得性突变。我们最近发现突变的KIT错误定位于高尔基体区域并启动不受控制的信号传导。然而，其高尔基体滞留的分子机制仍然未知。在这里，我们表明，蛋白激酶D2（PKD 2）被激活的突变体，这导致KIT的高尔基体保留。在PKD 2抑制细胞中，KIT从高尔基体区域迁移到溶酶体，随后发生降解。重要的是，离域KIT不能触发下游激活。在高尔基体区域，KIT通过磷脂酶γ2（PLCγ2）激活PKD 2-磷脂酰肌醇4-激酶III β（PKD 2-PI 4 KIII β）通路，产生富含PI 4 P的膜结构域，在此处异常募集AP 1-GGA 1复合物。在这个级联中的任何因素的破坏导致KIT从高尔基体区域释放，表明这些PKD 2相关的途径是负责KIT的高尔基体保留。我们的发现揭示了KIT错误定位的分子机制，并为抑制致癌信号的新策略提供了证据。
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 KIT’s 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-kinaseIIIβ (PKD2-PI4KIIIβ) pathway through phospholipase γ2 (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 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.