Nardilysin-Regulated Scission Mechanism Activates Polo-like Kinase 3 to Suppress the Development of Pancreatic Cancer

Fu, J.; Li, J.; Li, C.-F.; Tsai, C.-L.; Yin, W.; Hou, J.; Chen, P.; Cao, Y.; Kang, Y.; Sun, Y.; Xia, X.; Furukawa, K.; Lu, Y.; Wu, M.; Huang, Q.; Yao, J.; Hawke, D. H.; Pan, B.-F.; Zhao, J.; Huang, J.; Wang, H.; Bahassi, E. M.; Stambrook, P. J.; Huang, P.; Fleming, J. B.; Maitra, A. B.; Tainer, J.; Hung, M.-C.; Chiao, P.

doi:10.1101/2022.07.28.501759

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bioRxiv · 10.1101/2022.07.28.501759

Nardilysin-Regulated Scission Mechanism Activates Polo-like Kinase 3 to Suppress the Development of Pancreatic Cancer

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of apoptotic pathways. Here, we find that development of anoikis 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 contained 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) was quickly removed by proteasome degradation preventing the p41Plk3 inhibition by PBD. We found that p41Plk3 is the activated form of Plk3 that regulates a feedforward mechanism to promote anoikis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn, induces expression of Plk3 and pro-apoptotic genes. These findings uncovered an NRDC-regulated post-translational mechanism (PTM) that activates Plk3, establishing a prototypic regulation by scission mechanism.

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Fu, J., Li, J., Li, C.-F., Tsai, C.-L., Yin, W., Hou, J., Chen, P., Cao, Y., Kang, Y., Sun, Y., Xia, X., Furukawa, K., Lu, Y., Wu, M., Huang, Q., Yao, J., Hawke, D. H., Pan, B.-F., Zhao, J., Huang, J., Wang, H., Bahassi, E. M., Stambrook, P. J., Huang, P., Fleming, J. B., Maitra, A. B., Tainer, J., Hung, M.-C., Chiao, P.. 2022-07-30. Nardilysin-Regulated Scission Mechanism Activates Polo-like Kinase 3 to Suppress the Development of Pancreatic Cancer. https://doi.org/10.1101/2022.07.28.501759

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