Nature Communications (Apr 2024)
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,
- Paul J. Chiao
Affiliations
- Jie Fu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Jianhua Ling
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Ching-Fei Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Chi-Lin Tsai
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Wenjuan Yin
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Junwei Hou
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Ping Chen
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Yu Cao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Ya’an Kang
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center
- Yichen Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Xianghou Xia
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Zhou Jiang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Kenei Furukawa
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Yu Lu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Min Wu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Qian Huang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Jun Yao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- David H. Hawke
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center
- Bih-Fang Pan
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center
- Jun Zhao
- Department of Pathology, The University of Texas MD Anderson Cancer Center
- Jiaxing Huang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Huamin Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center
- E. I. Mustapha Bahassi
- Department of Molecular Genetics, University of Cincinnati Cancer Institute
- Peter J. Stambrook
- Department of Molecular Genetics, University of Cincinnati Cancer Institute
- Peng Huang
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center
- Jason B. Fleming
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center
- Anirban Maitra
- Department of Pathology, The University of Texas MD Anderson Cancer Center
- John A. Tainer
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Chunru Lin
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- Paul J. Chiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
- DOI
- https://doi.org/10.1038/s41467-024-47242-3
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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 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.
