2. Academic Validation
  3. LIMK1 as a Novel Kinase of β-Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5

LIMK1 as a Novel Kinase of β-Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5

  • Adv Sci (Weinh). 2025 Aug;12(29):e03223. doi: 10.1002/advs.202503223.
Shu-Jun Li 1 2,  Zhuo-Ran Liang 3,  Zhi-Chao Liu 4,  Xue-Ping Luo 5,  Jun-Yi Li 2,  Xiao-Mei Yu 2,  Xuan-Zhang Huang 6,  Yan He 2,  Tao-Yang Xu 2,  Jiao-Jiao Xu 1 2,  Shao-Cong Peng 2,  Yu-Xiang Song 1 2,  Yan He 1 2,  Xiao-Wan Zhuang 2,  Can-Can Zheng 2,  Fan Zhang 7,  Alfred King-Yin Lam 8,  Wei Dai 9,  Ming-Liang He 10,  Bo Liu 11,  Qi Zhao 12,  Guo-Liang Lu 13,  Jin-Bao Liu 1,  Zhen-Ning Wang 6,  Zhi-Gang Li 4,  Ze-Xian Liu 3,  Wen-Wen Xu 1,  Bin Li 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511495, China.
  • 2 State Key Laboratory of Respiratory Disease, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510700, China.
  • 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Guangzhou, 510060, China.
  • 4 Department of Thoracic Surgery, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
  • 5 Department of Thoracic Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 511495, China.
  • 6 Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110001, China.
  • 7 Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China.
  • 8 Cancer Molecular Pathology and Griffith Medical School, Griffith University, Gold Coast, Queensland, 4222, Australia.
  • 9 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 999077, China.
  • 10 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, 999077, China.
  • 11 Fujian Key Laboratory of Precision Medicine for Cancer, Department of Thoracic Surgery, Palmar Hyperhidrosis Research Institute, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350005, China.
  • 12 Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.
  • 13 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, and Maurice Wilkins Centre, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
PMID: 40476449 DOI: 10.1002/advs.202503223
Abstract

Metastasis is a major cause of Cancer deaths, but the underlying molecular mechanisms remain largely unknown. Esophageal squamous cell carcinoma (ESCC) is a highly aggressive Cancer with poor survival, yet the key kinases driving ESCC metastasis and their biological function have not been fully discovered. Here, a kinase-substrate map of metastatic ESCC is presented for the first time by conducting a phosphoproteomics analysis of 60 clinical specimens. By further consolidating data with CRISPR/Cas9 functional screening, LIM domain kinase 1 (LIMK1) is identified as a novel kinase of β-catenin. The in vitro and in vivo experiments demonstrated that LIMK1 cooperates with Cyclin-dependent kinase 5 (CDK5) to promote Cancer metastasis in a phosphorylation-dependent manner. Mechanistically, LIMK1 and CDK5 synergistically phosphorylate β-catenin at S191, enhancing its phosphorylation and interaction with Nucleoporin 93, resulting in β-catenin nuclear translocation and activation of key pathways in Cancer metastasis. High expression of LIMK1 and CDK5 is associated with poor prognosis of ESCC patients, and the clinical and functional significance of LIMK1/CDK5-Wnt/β-catenin axis is also verified in esophageal adenocarcinoma, gastric Cancer, and lung Cancer. Furthermore, the combination of LIMK1 and CDK5 inhibitors significantly suppresses metastasis in multiple models. This work highlights LIMK1 as a novel regulatory and targetable kinase of β-catenin, informing the treatment of advanced Cancer.

Keywords

LIMK1; esophageal squamous cell carcinoma; kinase‐substrate map; metastasis; β‐catenin.

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