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CDK5 通过磷酸化正向调节胰腺癌细胞中的 Notch1 信号通路。

CDK5 positively regulates Notch1 signaling in pancreatic cancer cells by phosphorylation.

机构信息

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.

Core Facilities for Molecular Biology, Capital Medical University, Beijing, China.

出版信息

Cancer Med. 2021 Jun;10(11):3689-3699. doi: 10.1002/cam4.3916. Epub 2021 May 7.

DOI:10.1002/cam4.3916
PMID:33960694
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8178504/
Abstract

The marked overexpression of cyclin-dependent kinase 5 (CDK5) or Notch1 receptor, which plays critical roles in pancreatic ductal adenocarcinoma (PDAC) development, has been detected in numerous PDAC cell lines and tissues. Although, a previous study has demonstrated that CDK5 inhibition disrupts Notch1 functions in human umbilical vein endothelial cells, the mechanism underlying Notch1 activation regulated by CDK5 remains unclear. Herein, we identified a physical interaction between CDK5 and Notch1 in PDAC cells, with the Notch1 peptide phosphorylated by CDK5/p25 kinase. CDK5 blockade resulted in the profound inhibition of Notch signaling. Accordingly, CDK5 inhibition sensitized PDAC cell proliferation and migration following Notch inhibition. In conclusion, CDK5 positively regulates Notch1 function via phosphorylation, which in turn promotes cell proliferation and migration. The combinational inhibition of CDK5 and Notch signaling may be an effective strategy in the treatment of PDAC.

摘要

细胞周期蛋白依赖性激酶 5（CDK5）或 Notch1 受体的过表达在胰腺导管腺癌（PDAC）的发展中起着关键作用，这在许多 PDAC 细胞系和组织中都有检测到。尽管之前的一项研究表明 CDK5 抑制会破坏人脐静脉内皮细胞中的 Notch1 功能，但 CDK5 调节 Notch1 激活的机制尚不清楚。在此，我们在 PDAC 细胞中鉴定到 CDK5 与 Notch1 之间的物理相互作用，CDK5/p25 激酶使 Notch1 肽磷酸化。CDK5 阻断导致 Notch 信号的深度抑制。相应地， Notch 抑制后，CDK5 抑制可显著增强 PDAC 细胞的增殖和迁移。总之，CDK5 通过磷酸化正向调节 Notch1 功能，进而促进细胞增殖和迁移。CDK5 和 Notch 信号的联合抑制可能是治疗 PDAC 的有效策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/2559b2577072/CAM4-10-3689-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/36df60169099/CAM4-10-3689-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/618e78924d5d/CAM4-10-3689-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/4c7f4f9f4412/CAM4-10-3689-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/7d94e363012b/CAM4-10-3689-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/2559b2577072/CAM4-10-3689-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/36df60169099/CAM4-10-3689-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/618e78924d5d/CAM4-10-3689-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/4c7f4f9f4412/CAM4-10-3689-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/7d94e363012b/CAM4-10-3689-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7fc/8178504/2559b2577072/CAM4-10-3689-g004.jpg

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本文引用的文献

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