Vaccinia-related kinase 2 drives pancreatic cancer progression by protecting Plk1 from Chfr-mediated degradation.
Oncogene
; 40(28): 4663-4674, 2021 07.
Article
em En
| MEDLINE
| ID: mdl-34140642
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas
/
Proteínas Serina-Treonina Quinases
/
Proteínas de Ciclo Celular
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article