Faculty, Staff and Student Publications
Publication Date
4-11-2024
Journal
Nature Communications
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.
Keywords
Humans, Mice, Animals, Proto-Oncogene Proteins p21(ras), Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Metalloendopeptidases, Pancreatic cancer, Post-translational modifications, Cell signalling, Kinases
DOI
10.1038/s41467-024-47242-3
PMID
38605037
PMCID
PMC11009390
PubMedCentral® Posted Date
April 2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Oncology Commons
Comments
Supplementary Material
PMID: 38605037