Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer

Jie Fu (), Jianhua Ling, Ching-Fei Li, Chi-Lin Tsai, Wenjuan Yin, Junwei Hou, Ping Chen, Yu Cao, Ya’an Kang, Yichen Sun, Xianghou Xia, Zhou Jiang, Kenei Furukawa, Yu Lu, Min Wu, Qian Huang, Jun Yao, David H. Hawke, Bih-Fang Pan, Jun Zhao, Jiaxing Huang, Huamin Wang, E. I. Mustapha Bahassi, Peter J. Stambrook, Peng Huang, Jason B. Fleming, Anirban Maitra, John A. Tainer, Mien-Chie Hung, Chunru Lin () and Paul J. Chiao ()
Additional contact information
Jie Fu: The University of Texas MD Anderson Cancer Center
Jianhua Ling: The University of Texas MD Anderson Cancer Center
Ching-Fei Li: The University of Texas MD Anderson Cancer Center
Chi-Lin Tsai: The University of Texas MD Anderson Cancer Center
Wenjuan Yin: The University of Texas MD Anderson Cancer Center
Junwei Hou: The University of Texas MD Anderson Cancer Center
Ping Chen: The University of Texas MD Anderson Cancer Center
Yu Cao: The University of Texas MD Anderson Cancer Center
Ya’an Kang: The University of Texas MD Anderson Cancer Center
Yichen Sun: The University of Texas MD Anderson Cancer Center
Xianghou Xia: The University of Texas MD Anderson Cancer Center
Zhou Jiang: The University of Texas MD Anderson Cancer Center
Kenei Furukawa: The University of Texas MD Anderson Cancer Center
Yu Lu: The University of Texas MD Anderson Cancer Center
Min Wu: The University of Texas MD Anderson Cancer Center
Qian Huang: The University of Texas MD Anderson Cancer Center
Jun Yao: The University of Texas MD Anderson Cancer Center
David H. Hawke: The University of Texas MD Anderson Cancer Center
Bih-Fang Pan: The University of Texas MD Anderson Cancer Center
Jun Zhao: The University of Texas MD Anderson Cancer Center
Jiaxing Huang: The University of Texas MD Anderson Cancer Center
Huamin Wang: The University of Texas MD Anderson Cancer Center
E. I. Mustapha Bahassi: University of Cincinnati Cancer Institute
Peter J. Stambrook: University of Cincinnati Cancer Institute
Peng Huang: The University of Texas MD Anderson Cancer Center
Jason B. Fleming: The University of Texas MD Anderson Cancer Center
Anirban Maitra: The University of Texas MD Anderson Cancer Center
John A. Tainer: The University of Texas MD Anderson Cancer Center
Mien-Chie Hung: The University of Texas MD Anderson Cancer Center
Chunru Lin: The University of Texas MD Anderson Cancer Center
Paul J. Chiao: The University of Texas MD Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.

Date: 2024
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DOI: 10.1038/s41467-024-47242-3

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