TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ
TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ
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TOPK 通过磷酸化 ULK1 抑制自噬并促进神经胶质瘤对 TMZ 的抵抗
DOI：
10.1038/s41419-019-1805-9
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发表时间：
2019-08-05
影响因子：
9
通讯作者：
Zhu, Feng
中科院分区：
文献类型：
--
作者：
Lu, Hui;Xiao, Juanjuan;Zhu, Feng
ULK 1是ULK 1复合物的最上层蛋白，正在成为自噬诱导的关键节点。然而，ULK 1的调控尚未完全了解。在这项研究中，我们确定TOPK（T-LAK细胞起源的蛋白激酶），一种癌激酶，作为一种新的上游激酶磷酸化ULK 1。我们发现TOPK可以直接与ULK 1在Ser 469，Ser 495和Ser 533处结合并磷酸化。通过TOPK使ULK 1在Ser 469、Ser 495和Ser 533处的磷酸化降低ULK 1的活性和稳定性。此外，我们想检查自噬的启动，因为ULK 1的还原活性减少了自噬的发生。我们证明TOPK可以抑制胶质瘤细胞自噬的启动和发展。此外，TOPK抑制增加胶质瘤细胞对替莫唑胺（TMZ）的敏感性。这一发现提供了对GBM治疗中TMZ抗性问题的深入了解。
ULK1, the upper-most protein of the ULK1 complex, is emerging as a crucial node in autophagy induction. However, the regulation of ULK1 is not fully understood. In this study, we identified TOPK (T-LAK cell-originated protein kinase), an oncokinase, as a novel upstream kinase to phosphorylate ULK1. We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1. In addition, we want to examine the initiation of autophagy because the reduction activity of ULK1 reduces the occurrence of autophagy. We demonstrated that TOPK could inhibit the initiation and progression of autophagy in glioma cells. Furthermore, TOPK inhibition increased the sensitivity of glioma cells to temozolomide (TMZ). This discovery provides insight into the problem of TMZ-resistance in GBM treatment.