Vaccinia-related kinase 2 drives pancreatic cancer progression by protecting Plk1 from Chfr-mediated degradation.

Abstract

As a key cell cycle regulator, polo-like kinase 1 (Plk1) has been recognized as a crucial factor involved in the progression of pancreatic cancer (PC). However, its regulatory mechanism is poorly understood. Here, we present evidence that Plk1 is a novel substrate of vaccinia-related kinase 2 (VRK2), a serine-threonine kinase that is highly expressed and predicts poor prognosis in PC. VRK2 phosphorylates Plk1 at threonine 210 and protects it from ubiquitin-dependent proteasomal degradation. We showed that mechanistically complement factor H-related protein (CFHR), as a major E3 ligase, promotes Plk1 degradation by ubiquitinating it at lysine 209. Phosphorylation of Plk1 at threonine 210 by VRK2 interferes with the interaction of Chfr with Plk1 and antagonizes Plk1 ubiquitination, thereby stabilizing the Plk1 protein. Taken together, our data reveal a mechanism of Plk1 overexpression in PC and provide evidence for targeting VRK2 as a potential therapeutic strategy.

• Authors: Hengqing Zhu, Qing Li, Yulan Zhao, Hong Peng, Liangyun Guo, Jing Zhu, Zi Jiang, Zhaoxia Zeng, Bin Xu, Sisi Chen
• Journal: Oncogene (Oncogene) Vol. 40 Issue 28 Pg. 4663-4674 (07 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 34140642 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Cell Cycle Proteins
• Proto-Oncogene Proteins
• Protein Serine-Threonine Kinases
• polo-like kinase 1

Topics

• Cell Cycle Proteins
• Pancreas
• Pancreatic Neoplasms
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins
• Vaccinia