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

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.

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Publication Details

Journal
Advanced Science
Published
2025-06-06
DOI
https://doi.org/10.1002/advs.202503223
Citations
2
Primary Topic
Cancer-related Molecular Pathways
Type
article
Field-Weighted Citation Impact
2.09

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article

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

Xingju Luo, Alfred K. Lam, Tao‐Yang Xu, Zhuoran Liang et al.
2 citations
Advanced Science
Cancer-related Molecular Pathways
2.09
article

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

Xingju Luo, Alfred K. Lam, Tao‐Yang Xu, Zhuoran Liang, Zexian Liu, Qi Zhao, Can‐Can Zheng, Zhenning Wang, Zhi‐Chao Liu, Xiaomei Yu, Guo‐Liang Lu, Ming‐Liang He, Xiaoying Zhuang, Xuanzhang Huang, Jun‐Yi Li, Zhigang Li, Bin Li, Fan Zhang, Bo Liu, Wei Dai, Shujun Li, Yan He, Jiaojiao Xu, Peng Shen, Wenwen Xu, Yuxiang Song, Jinbao Liu
article en
2 citations

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.

Advanced ScienceVol. 12(29)
Griffith University (AU), Fujian Medical University (CN), University of Auckland (NZ), Sun Yat-sen University (CN), Henan University of Science and Technology (CN), City University of Hong Kong (HK), Chinese University of Hong Kong (HK), Shanghai Jiao Tong University (CN), University of Macau (MO), Shanghai Chest Hospital (CN), Second Affiliated Hospital of Guangzhou Medical University (CN), Cancer Society of New Zealand (NZ), First Affiliated Hospital of Fujian Medical University (CN), Maurice Wilkins Centre (NZ), First Hospital of China Medical University (CN), Sun Yat-sen University Cancer Center (CN), State Key Laboratory of Respiratory Disease (CN), University of Hong Kong (HK), China Medical University (CN), Guangzhou Medical University (CN)
National Natural Science Foundation of China, National Outstanding Youth Science Fund Project of National Natural Science Foundation of China, National Key Research and Development Program of China
Good health and well-being
Openalex Percentile: Top 12%
Cancer-related Molecular Pathways
2.09
DOIOpen Access PDFOpenAlex
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