自噬
ULK1
磷酸化
癌症研究
程序性细胞死亡
自噬相关蛋白13
细胞生物学
激酶
PI3K/AKT/mTOR通路
蛋白激酶A
袋3
细胞凋亡
癌细胞
ATG5型
下调和上调
化学
生物
mTORC1型
癌症
基因敲除
河马信号通路
蛋白激酶B
信号转导
作者
Guanman Li,Lei Li,Mengqing Li,Xu Chen,Qiao Su,Zhijuan Deng,Haibo Liu,Bin Li,Wen-Hui Zhang,Yongxu Jia,Wenjian Wang,Jie-Yi Ma,Hai-Liang Zhang,Dan Xie,Xiao Feng Zhu,Yulong He,Xin Yuan Guan,Jiong Bi
标识
DOI:10.1038/s41418-020-00627-5
摘要
Dysregulation of the balance between cell proliferation and cell death is a central feature of malignances. Death-associated protein kinase 3 (DAPK3) regulates programmed cell death including apoptosis and autophagy. Our previous study showed that DAPK3 downregulation was detected in more than half of gastric cancers (GCs), which was related to tumor invasion, metastasis, and poor prognosis. However, the precise molecular mechanism underlying DAPK3-mediated tumor suppression remains unclear. Here, we showed that the tumor suppressive function of DAPK3 was dependent on autophagy process. Mass spectrometry, in vitro kinase assay, and immunoprecipitation revealed that DAPK3 increased ULK1 activity by direct ULK1 phosphorylation at Ser556. ULK1 phosphorylation by DAPK3 facilitates the ULK1 complex formation, the VPS34 complex activation, and autophagy induction upon starvation. The kinase activity of DAPK3 and ULK1 Ser556 phosphorylation were required for DAPK3-modulated tumor suppression. The coordinate expression of DAPK3 with ULK1 Ser556 phosphorylation was confirmed in clinical GC samples, and this co-expression was correlated with favorable survival outcomes in patients. Collectively, these findings indicate that the tumor-suppressor roles of DAPK3 in GC are associated with autophagy and that DAPK3 is a novel autophagy regulator, which can directly phosphorylate ULK1 and activate ULK1. Thus, DAPK3 might be a promising prognostic autophagy-associated marker.
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