ERK-USP9X-coupled regulation of thymidine kinase 1 promotes both its enzyme activity-dependent and its enzyme activity-independent functions for tumor growth

Jingjing Tao; Zheng Wang; Rongkai Shi; Liming Lin; Min Li; Ying Meng; Shudi Luo; Xiaoming Jiang; Zhanpeng Guo; Yongfeng Shang; Zhimin Lu

doi:10.1038/s41594-024-01473-6

ERK-USP9X-coupled regulation of thymidine kinase 1 promotes both its enzyme activity-dependent and its enzyme activity-independent functions for tumor growth

Nat Struct Mol Biol. 2025 Jan 17. doi: 10.1038/s41594-024-01473-6. Online ahead of print.

Authors

Jingjing Tao^#^{1

2

3}, Zheng Wang^#^{4

5

6}, Rongkai Shi^#^{1

2

3}, Liming Lin^{1

2

3}, Min Li^{1

2

3}, Ying Meng^{1

2

3}, Shudi Luo^{1

2

3}, Xiaoming Jiang^{1

2

3}, Zhanpeng Guo^{1

2

3}, Yongfeng Shang⁷, Zhimin Lu^{8

9

10

11}

Affiliations

¹ Zhejiang Provincial Key Laboratory of Pancreatic Disease, Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University, Hangzhou, China.
³ Cancer Center, Zhejiang University, Hangzhou, China.
⁴ Zhejiang Provincial Key Laboratory of Pancreatic Disease, Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
⁵ Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University, Hangzhou, China. [email protected].
⁶ Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
⁷ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. [email protected].
⁸ Zhejiang Provincial Key Laboratory of Pancreatic Disease, Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
⁹ Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University, Hangzhou, China. [email protected].
¹⁰ Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
¹¹ Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, China. [email protected].

^# Contributed equally.

PMID: 39824978
DOI: 10.1038/s41594-024-01473-6

Abstract

Thymidine kinase 1 (TK1), a crucial enzyme in DNA synthesis, is highly expressed in various cancers. However, the mechanisms underlying its elevated expression and the implications for tumor metabolism remain unclear. Here we demonstrate that activation of growth factor receptors enhances TK1 expression. Treatment with epidermal growth factor or insulin-like growth factor 1 induces the binding of ERK1/2 to TK1 and subsequent TK1 S13/231 phosphorylation by ERK1/2. This modification recruits ubiquitin carboxyl-terminal hydrolase 9X to deubiquitylate TK1, preventing its proteasomal degradation. Stabilized TK1 not only enhances its enzyme activity-dependent deoxythymidine monophosphate production for DNA synthesis but also promotes glycolysis independently of its enzymatic activity by upregulating phosphofructokinase/fructose bisphosphatase type 3 expression. This dual role of TK1 drives the proliferation of human hepatocellular carcinoma cells and liver tumor growth in mice. Our findings reveal a crucial mechanism by which growth factors promote tumor development through TK1-mediated DNA synthesis and glycolysis and highlight TK1 as a potential molecular target for cancer treatment.