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  3. Serine/threonine/tyrosine kinase 1 drives pancreatic carcinogenesis via GSK3β sequestration-mediated Wnt/β-catenin pathway hyperactivation

Serine/threonine/tyrosine kinase 1 drives pancreatic carcinogenesis via GSK3β sequestration-mediated Wnt/β-catenin pathway hyperactivation

  • Signal Transduct Target Ther. 2025 Jun 30;10(1):205. doi: 10.1038/s41392-025-02292-x.
Cefan Zhou # 1 2,  Xueying Dong # 1,  Shi Li # 1,  Yue Xi 1,  Yuan Liu 1,  Xuehong Qian 1,  Ziyan Song 1,  Li Zhou 3,  Rui Zhang 1,  Hao Lyu 1,  Shuai Xiao 1,  Dong Guo 1,  Qi Zhang 1,  Weiyong Liu 4,  Yan Xiong 5,  Zhentian Wang 6,  Chaojun Yan 1,  Zijian Zhang 1,  Haichuan Zhu 1,  Xing-Zhen Chen 2,  Zhiyin Song 7,  Jingfeng Tang 8 9
Affiliations

Affiliations

  • 1 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China.
  • 2 Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • 3 Animal Biosafety Level III Laboratory at the Center for Animal Experiment, Wuhan University, Wuhan, China.
  • 4 Department of Clinical Laboratory, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, Wuhan, China.
  • 6 Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, and Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
  • 7 Department of Pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China.
  • 8 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China. Jingfeng_hut@163.com.
  • 9 Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada. Jingfeng_hut@163.com.
  • # Contributed equally.
PMID: 40588478 DOI: 10.1038/s41392-025-02292-x
Abstract

The Wnt/β-catenin pathway is strongly relevant to pancreatic Cancer progression, poor prognostic outcomes, and elevated cancer-related mortality. However, the mechanism underlying continuously activated Wnt/β-catenin signaling in pancreatic Cancer, a context in which adenomatous polyposis coli (APC) mutations are rarely observed, remains poorly understood. In this study, we investigated the role of STYK1 in regulating canonical Wnt/β-catenin signaling and pancreatic Cancer tumorigenesis using the LSL-KrasG12D; Trp53R172H/+; Pdx1Cre mouse model. Our findings demonstrate that STYK1 directly binds to β-catenin and GSK3β, inhibiting GSK3β activity by increasing the level of its kinase-inactive form, which is phosphorylated at S9, and promoting its sequestration into MVBs. We further showed that STYK1-mediated GSK3β sequestration is impaired by Autophagy inhibitors or in Atg7 knockout cells, linking this process to autophagic regulation. Structural analysis identified conserved tyrosine-based (Y191QRL194) and dileucine-based (GDLL203-204) sorting motifs in STYK1, which facilitate clathrin/AP2-dependent internalization essential for GSK3β sequestration. The phosphorylation of STYK1 at Y191 by Blk kinase enhances its interaction with AP2, thereby accelerating GSK3β sequestration and subsequent Wnt/β-catenin pathway activation. Notably, inhibitory peptides targeting either the STYK1-β-catenin or the STYK1-GSK3β interface significantly suppressed pancreatic Cancer development in vitro and in vivo, underscoring their therapeutic potential. Collectively, these results elucidate a novel STYK1-driven mechanism for Wnt/β-catenin activation in APC-independent pancreatic Cancer and provide preclinical evidence for targeting STYK1-mediated signaling as a therapeutic strategy.

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