Creatine Kinase B Suppresses Ferroptosis by Phosphorylating GPX4 Through a Moonlighting Function

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2023 May 8

PMID 37156912

Authors

Ke Wu

Meisi Yan

Tong Liu

Zheng Wang

Yuran Duan

Yan Xia

Guimei Ji

Yuli Shen

Lei Wang

Lin Li

Peixiang Zheng

Bofei Dong

Qingang Wu

Liwei Xiao

Xueying Yang

Haochen Shen

Ting Wen

Jingjing Zhang

Jinfeng Yi

Yuhan Deng

Xu Qian

Leina Ma

Jing Fang

Qin Zhou

Zhimin Lu

Daqian Xu

Affiliations

Soon will be listed here.

Abstract

Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.

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