학술논문
Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer
Document Type
article
Author
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
Source
Nature Communications, Vol 15, Iss 1, Pp 1-19 (2024)
Subject
Language
English
ISSN
2041-1723
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 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.