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

Author

Listed:
  • Jie Fu

    (The University of Texas MD Anderson Cancer Center)

  • Jianhua Ling

    (The University of Texas MD Anderson Cancer Center)

  • Ching-Fei Li

    (The University of Texas MD Anderson Cancer Center)

  • Chi-Lin Tsai

    (The University of Texas MD Anderson Cancer Center)

  • Wenjuan Yin

    (The University of Texas MD Anderson Cancer Center)

  • Junwei Hou

    (The University of Texas MD Anderson Cancer Center)

  • Ping Chen

    (The University of Texas MD Anderson Cancer Center)

  • Yu Cao

    (The University of Texas MD Anderson Cancer Center)

  • Ya’an Kang

    (The University of Texas MD Anderson Cancer Center)

  • Yichen Sun

    (The University of Texas MD Anderson Cancer Center)

  • Xianghou Xia

    (The University of Texas MD Anderson Cancer Center)

  • Zhou Jiang

    (The University of Texas MD Anderson Cancer Center)

  • Kenei Furukawa

    (The University of Texas MD Anderson Cancer Center)

  • Yu Lu

    (The University of Texas MD Anderson Cancer Center)

  • Min Wu

    (The University of Texas MD Anderson Cancer Center)

  • Qian Huang

    (The University of Texas MD Anderson Cancer Center)

  • Jun Yao

    (The University of Texas MD Anderson Cancer Center)

  • David H. Hawke

    (The University of Texas MD Anderson Cancer Center)

  • Bih-Fang Pan

    (The University of Texas MD Anderson Cancer Center)

  • Jun Zhao

    (The University of Texas MD Anderson Cancer Center)

  • Jiaxing Huang

    (The University of Texas MD Anderson Cancer Center)

  • Huamin Wang

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences)

  • E. I. Mustapha Bahassi

    (University of Cincinnati Cancer Institute)

  • Peter J. Stambrook

    (University of Cincinnati Cancer Institute)

  • Peng Huang

    (The University of Texas MD Anderson Cancer Center
    Sun Yat-sen University Cancer Center)

  • Jason B. Fleming

    (The University of Texas MD Anderson Cancer Center
    Moffitt Cancer Center)

  • Anirban Maitra

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences)

  • John A. Tainer

    (The University of Texas MD Anderson Cancer Center)

  • Mien-Chie Hung

    (The University of Texas MD Anderson Cancer Center
    China Medical University)

  • Chunru Lin

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences)

  • Paul J. Chiao

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences)

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 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.

Suggested Citation

  • 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, 2024. "Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47242-3
    DOI: 10.1038/s41467-024-47242-3
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