Hippo signaling promotes JNK-dependent cell migration.
Overwhelming studies show that dysregulation of the Hippo pathway is positively correlated with cell proliferation, growth, and tumorigenesis. Paradoxically, the detailed molecular roles of the Hippo pathway in cell invasion remain debatable. Using aDrosophilainvasion model in wing epithelium, we show herein that activated Hippo signaling promotes cell invasion and epithelial-mesenchymal transition through JNK, as inhibition of JNK signaling dramatically blocked Hippo pathway activation-induced matrix metalloproteinase 1 expression and cell invasion. Furthermore, we identifybantam-Rox8 modules as essential components downstream of Yorkie in mediating JNK-dependent cell invasion. Finally, we confirm that YAP (Yes-associated protein) expression negatively regulates TIA1 (Rox8 ortholog) expression and cell invasion in human cancer cells. Together, these findings provide molecular insights into Hippo pathway-mediated cell invasion and also raise a noteworthy concern in therapeutic interventions of Hippo-related cancers, as simply inhibiting Yorkie or YAP activity might paradoxically accelerate cell invasion and metastasis.
Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China; xianjue.ma@yale.edu zxpkxy@126.com juxiangchen.cz@gmail.com lei.xue@tongji.edu.cn.|Department of Genetics, Yale School of Medicine, New Haven, CT 06536.|Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06536.
Xianjue
X
Ma
Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Hongxiang
H
Wang
Radiology Department and Interventional Radiology Center, Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China.
Jiansong
J
Ji
Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
Wenyan
W
Xu
Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
Yihao
Y
Sun
Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
Wenzhe
W
Li
Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China; xianjue.ma@yale.edu zxpkxy@126.com juxiangchen.cz@gmail.com lei.xue@tongji.edu.cn.
Xiaoping
X
Zhang
Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; xianjue.ma@yale.edu zxpkxy@126.com juxiangchen.cz@gmail.com lei.xue@tongji.edu.cn.
Juxiang
J
Chen
Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China; xianjue.ma@yale.edu zxpkxy@126.com juxiangchen.cz@gmail.com lei.xue@tongji.edu.cn.
Lei
L
Xue
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000074019:T-Cell Intracellular Antigen-1 / Q000235:genetics* / Q000378:metabolism; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D035683:MicroRNAs; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; D015534:Trans-Activators; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C082968:Rox8 protein, Drosophila; C071558:TIA1 protein, human; C088374:YAP1 protein, human; C503814:Yki protein, Drosophila; C471146:bantam microRNA, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases
Drosophila; Hippo; JNK; Rox8; migration