2. Academic Validation
  3. Deciphering the clinical significance and kinase functions of GSK3α in colon cancer by proteomics and phosphoproteomics

Deciphering the clinical significance and kinase functions of GSK3α in colon cancer by proteomics and phosphoproteomics

  • Mol Cell Proteomics. 2023 Apr 7;100545. doi: 10.1016/j.mcpro.2023.100545.
Li Gao 1,  Ying Lu 1,  Hai-Ning Chen 2,  Zhigui Li 3,  Meng Hu 1,  Rou Zhang 1,  Xiuxuan Wang 1,  Zhiqiang Xu 1,  Yanqiu Gong 1,  Rui Wang 4,  Dan Du 4,  Shan Hai 1,  Shuangqing Li 1,  Dan Su 1,  Yuan Li 5,  Heng Xu 1,  Zong-Guang Zhou 6,  Lunzhi Dai 7
Affiliations

Affiliations

  • 1 National Clinical Research Center for Geriatrics and General Practice Ward/International Medical Center Ward, General Practice Medical Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 4 Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 5 Institute of Digestive Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 6 Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Digestive Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 7 National Clinical Research Center for Geriatrics and General Practice Ward/International Medical Center Ward, General Practice Medical Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 37031867 DOI: 10.1016/j.mcpro.2023.100545
Abstract

GSK3α and GSK3β are two GSK3 isoforms with 84% overall identity and 98% identity in their catalytic domains. GSK3β plays important roles in the pathogenesis of Cancer, while GSK3α has long been considered a functionally redundant protein of GSK3β. Few studies have specifically investigated the functions of GSK3α. In this study, unexpectedly, we found that the expression of GSK3α, but not GSK3β, was significantly correlated with the overall survival (OS) of colon Cancer patients in 4 independent cohorts. To decipher the roles of GSK3α in colon Cancer, we profiled the phosphorylation substrates of GSK3α and uncovered 156 phosphosites from 130 proteins specifically regulated by GSK3α. A number of these GSK3α-mediated phosphosites have never been reported before or have been incorrectly identified as substrates of GSK3β. Among them, the levels of HSF1S303p, CANXS583p, MCM2S41p, POGZS425p, SRRM2T983p and PRPF4BS431p were significantly correlated with the OS of colon Cancer patients. Further pull-down assays identified 23 proteins, such as THRAP3, BCLAF1 and STAU1, showing strong binding affinity to GSK3α. The interaction between THRAP3 and GSK3α was verified by biochemical experiments. Notably, among the 18 phosphosites of THRAP3, phosphorylation at S248, S253 and S682 is specifically mediated by GSK3α. Mutation of S248 to D (S248D), which mimics the effect of phosphorylation, obviously increased Cancer cell migration and the binding affinity to proteins related to DNA damage repair. Collectively, this work not only discloses the specific function of GSK3α as a kinase but also suggests GSK3α as a promising therapeutic target for colon Cancer.

Keywords

Colon cancer; GSK3α; GSK3β; phosphorylation; substrate specificity.

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