Hippo signaling promotes JNK-dependent cell migration

Xianjue Ma; Hongxiang Wang; Jiansong Ji; Wenyan Xu; Yihao Sun; Wenzhe Li; Xiaoping Zhang; Juxiang Chen; Lei Xue

doi:10.1073/pnas.1621359114

Hippo signaling promotes JNK-dependent cell migration

Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):1934-1939. doi: 10.1073/pnas.1621359114. Epub 2017 Feb 7.

Authors

Xianjue Ma^{1

2

3}, Hongxiang Wang⁴, Jiansong Ji⁵, Wenyan Xu⁶, Yihao Sun⁶, Wenzhe Li⁶, Xiaoping Zhang¹, Juxiang Chen⁷, Lei Xue¹

Affiliations

¹ 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; [email protected] [email protected] [email protected] [email protected].
² Department of Genetics, Yale School of Medicine, New Haven, CT 06536.
³ Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06536.
⁴ Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
⁵ Radiology Department and Interventional Radiology Center, Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China.
⁶ 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.
⁷ Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; [email protected] [email protected] [email protected] [email protected].

Abstract

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.

Keywords: Drosophila; Hippo; JNK; Rox8; migration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Apoptosis / genetics
Carcinogenesis / genetics
Carcinogenesis / pathology
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
Disease Models, Animal
Drosophila Proteins / genetics*
Drosophila Proteins / metabolism
Drosophila melanogaster / 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
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 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
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Drosophila Proteins
Intracellular Signaling Peptides and Proteins
MicroRNAs
Nuclear Proteins
Phosphoproteins
RNA, Small Interfering
RNA-Binding Proteins
Rox8 protein, Drosophila
T-Cell Intracellular Antigen-1
TIA1 protein, human
Trans-Activators
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
Yki protein, Drosophila
bantam microRNA, Drosophila
Protein Serine-Threonine Kinases
hpo protein, Drosophila
JNK Mitogen-Activated Protein Kinases
Matrix Metalloproteinase 1