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

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2024年4月11日

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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,
Paul J. Chiao

摘要

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 Kras^G12D-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.