Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer
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Published:2024-04-11
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Fu JieORCID, Ling Jianhua, Li Ching-FeiORCID, Tsai Chi-LinORCID, Yin Wenjuan, Hou JunweiORCID, Chen Ping, Cao Yu, Kang Ya’an, Sun Yichen, Xia XianghouORCID, Jiang ZhouORCID, Furukawa Kenei, Lu Yu, Wu Min, Huang Qian, Yao Jun, Hawke David H., Pan Bih-Fang, Zhao Jun, Huang Jiaxing, Wang HuaminORCID, Bahassi E. I. Mustapha, Stambrook Peter J., Huang Peng, Fleming Jason B., Maitra AnirbanORCID, Tainer John A.ORCID, Hung Mien-ChieORCID, Lin ChunruORCID, Chiao Paul J.ORCID
Abstract
AbstractPancreatic 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.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute
Publisher
Springer Science and Business Media LLC
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