Hippo signaling promotes JNK-dependent cell migration

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 8; pp. 1934 - 1939
• Main Authors: Ma, Xianjue, Wang, Hongxiang, Ji, Jiansong, Xu, Wenyan, Sun, Yihao, Li, Wenzhe, Zhang, Xiaoping, Chen, Juxiang, Xu, Lei
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21.02.2017
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis - genetics; Biological Sciences; Cancer; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell growth; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; Cellular biology; Disease Models, Animal; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Matrix Metalloproteinase 1 - genetics; Matrix Metalloproteinase 1 - metabolism; Metastasis; MicroRNAs - genetics; MicroRNAs - metabolism; Microscopy, Fluorescence; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neoplasms - genetics; Neoplasms - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Protein expression; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; RNA Interference; RNA, Small Interfering - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal Transduction - genetics; T-Cell Intracellular Antigen-1 - genetics; T-Cell Intracellular Antigen-1 - metabolism; Tissue Array Analysis; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors; Tumorigenesis; migration; Rox8; Drosophila; Hippo; JNK
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1621359114

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 a Drosophila invasion 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 identify bantam-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.