LIMK1 as a Novel Kinase of β‐Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5
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 f...
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Wiley
2025-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202503223 |
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| author | Shu‐Jun Li Zhuo‐Ran Liang Zhi‐Chao Liu Xue‐Ping Luo Jun‐Yi Li Xiao‐Mei Yu Xuan‐Zhang Huang Yan He Tao‐Yang Xu Jiao‐Jiao Xu Shao‐Cong Peng Yu‐Xiang Song Yan He Xiao‐Wan Zhuang Can‐Can Zheng Fan Zhang Alfred King‐Yin Lam Wei Dai Ming‐Liang He Bo Liu Qi Zhao Guo‐Liang Lu Jin‐Bao Liu Zhen‐Ning Wang Zhi‐Gang Li Ze‐Xian Liu Wen‐Wen Xu Bin Li |
| author_facet | Shu‐Jun Li Zhuo‐Ran Liang Zhi‐Chao Liu Xue‐Ping Luo Jun‐Yi Li Xiao‐Mei Yu Xuan‐Zhang Huang Yan He Tao‐Yang Xu Jiao‐Jiao Xu Shao‐Cong Peng Yu‐Xiang Song Yan He Xiao‐Wan Zhuang Can‐Can Zheng Fan Zhang Alfred King‐Yin Lam Wei Dai Ming‐Liang He Bo Liu Qi Zhao Guo‐Liang Lu Jin‐Bao Liu Zhen‐Ning Wang Zhi‐Gang Li Ze‐Xian Liu Wen‐Wen Xu Bin Li |
| author_sort | Shu‐Jun Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d0943660766f4ee8a66cf1fc6ec867a6 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-d0943660766f4ee8a66cf1fc6ec867a62025-08-20T03:41:08ZengWileyAdvanced Science2198-38442025-08-011229n/an/a10.1002/advs.202503223LIMK1 as a Novel Kinase of β‐Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5Shu‐Jun Li0Zhuo‐Ran Liang1Zhi‐Chao Liu2Xue‐Ping Luo3Jun‐Yi Li4Xiao‐Mei Yu5Xuan‐Zhang Huang6Yan He7Tao‐Yang Xu8Jiao‐Jiao Xu9Shao‐Cong Peng10Yu‐Xiang Song11Yan He12Xiao‐Wan Zhuang13Can‐Can Zheng14Fan Zhang15Alfred King‐Yin Lam16Wei Dai17Ming‐Liang He18Bo Liu19Qi Zhao20Guo‐Liang Lu21Jin‐Bao Liu22Zhen‐Ning Wang23Zhi‐Gang Li24Ze‐Xian Liu25Wen‐Wen Xu26Bin Li27State Key Laboratory of Respiratory DiseaseGuangdong Provincial Key Laboratory of Protein Modification and DegradationSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou 511495 ChinaState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer Center, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and TechnologyGuangzhou 510060 ChinaDepartment of Thoracic SurgeryShanghai Chest HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200030 ChinaDepartment of Thoracic SurgeryThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 511495 ChinaState Key Laboratory of Respiratory DiseaseKey Laboratory of Biological Targeting DiagnosisTherapy and Rehabilitation of Guangdong Higher Education Institutesthe Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510700 ChinaState Key Laboratory of Respiratory DiseaseKey Laboratory of Biological Targeting DiagnosisTherapy and Rehabilitation of Guangdong Higher Education Institutesthe Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510700 ChinaDepartment of Surgical Oncology and General Surgery, The First Hospital of China Medical UniversityKey Laboratory of Precision Diagnosis and Treatment of Gastrointestinal TumorsMinistry of EducationChina Medical UniversityShenyang 110001 ChinaState Key Laboratory of Respiratory DiseaseKey Laboratory of Biological Targeting DiagnosisTherapy and Rehabilitation of Guangdong Higher Education Institutesthe Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510700 ChinaState Key Laboratory of Respiratory DiseaseKey Laboratory of Biological Targeting DiagnosisTherapy and Rehabilitation of Guangdong Higher Education Institutesthe Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510700 ChinaState Key Laboratory of Respiratory DiseaseGuangdong Provincial Key Laboratory of Protein Modification and DegradationSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou 511495 ChinaState Key Laboratory of Respiratory DiseaseKey Laboratory of Biological Targeting DiagnosisTherapy and Rehabilitation of Guangdong Higher Education Institutesthe Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510700 ChinaState Key Laboratory of Respiratory DiseaseGuangdong Provincial Key Laboratory of Protein Modification and DegradationSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou 511495 ChinaState Key Laboratory of Respiratory DiseaseGuangdong Provincial Key Laboratory of Protein Modification and DegradationSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou 511495 ChinaState Key Laboratory of Respiratory DiseaseKey Laboratory of Biological Targeting DiagnosisTherapy and Rehabilitation of Guangdong Higher Education Institutesthe Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510700 ChinaState Key Laboratory of Respiratory DiseaseKey Laboratory of Biological Targeting DiagnosisTherapy and Rehabilitation of Guangdong Higher Education Institutesthe Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510700 ChinaDepartment of Gastrointestinal SurgeryThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510700 ChinaCancer Molecular Pathology and Griffith Medical SchoolGriffith UniversityGold Coast Queensland 4222 AustraliaDepartment of Clinical OncologyLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong 999077 ChinaDepartment of Biomedical SciencesCity University of Hong KongHong Kong 999077 ChinaFujian Key Laboratory of Precision Medicine for CancerDepartment of Thoracic SurgeryPalmar Hyperhidrosis Research InstituteFirst Affiliated Hospital of Fujian Medical UniversityFuzhou Fujian 350005 ChinaFaculty of Health SciencesUniversity of MacauMacau SAR 999078 ChinaAuckland Cancer Society Research CentreFaculty of Medical and Health Sciencesand Maurice Wilkins CentreThe University of AucklandPrivate Bag 92019Auckland1142New ZealandState Key Laboratory of Respiratory DiseaseGuangdong Provincial Key Laboratory of Protein Modification and DegradationSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou 511495 ChinaDepartment of Surgical Oncology and General Surgery, The First Hospital of China Medical UniversityKey Laboratory of Precision Diagnosis and Treatment of Gastrointestinal TumorsMinistry of EducationChina Medical UniversityShenyang 110001 ChinaDepartment of Thoracic SurgeryShanghai Chest HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200030 ChinaState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer Center, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and TechnologyGuangzhou 510060 ChinaState Key Laboratory of Respiratory DiseaseGuangdong Provincial Key Laboratory of Protein Modification and DegradationSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou 511495 ChinaState Key Laboratory of Respiratory DiseaseKey Laboratory of Biological Targeting DiagnosisTherapy and Rehabilitation of Guangdong Higher Education Institutesthe Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510700 ChinaAbstract 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.https://doi.org/10.1002/advs.202503223esophageal squamous cell carcinomakinase‐substrate mapLIMK1metastasisβ‐catenin |
| spellingShingle | Shu‐Jun Li Zhuo‐Ran Liang Zhi‐Chao Liu Xue‐Ping Luo Jun‐Yi Li Xiao‐Mei Yu Xuan‐Zhang Huang Yan He Tao‐Yang Xu Jiao‐Jiao Xu Shao‐Cong Peng Yu‐Xiang Song Yan He Xiao‐Wan Zhuang Can‐Can Zheng Fan Zhang Alfred King‐Yin Lam Wei Dai Ming‐Liang He Bo Liu Qi Zhao Guo‐Liang Lu Jin‐Bao Liu Zhen‐Ning Wang Zhi‐Gang Li Ze‐Xian Liu Wen‐Wen Xu Bin Li LIMK1 as a Novel Kinase of β‐Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5 Advanced Science esophageal squamous cell carcinoma kinase‐substrate map LIMK1 metastasis β‐catenin |
| title | LIMK1 as a Novel Kinase of β‐Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5 |
| title_full | LIMK1 as a Novel Kinase of β‐Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5 |
| title_fullStr | LIMK1 as a Novel Kinase of β‐Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5 |
| title_full_unstemmed | LIMK1 as a Novel Kinase of β‐Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5 |
| title_short | LIMK1 as a Novel Kinase of β‐Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5 |
| title_sort | limk1 as a novel kinase of β catenin promotes esophageal cancer metastasis by cooperating with cdk5 |
| topic | esophageal squamous cell carcinoma kinase‐substrate map LIMK1 metastasis β‐catenin |
| url | https://doi.org/10.1002/advs.202503223 |
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