1. MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway
- Author
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Yun Zhao, Huixiong Xu, Min Chen, Chun Hou, Wenjia Wang, Pingping Nie, Shi Jiao, Liwei An, Zhaocai Zhou, Hui Zhang, Yang Tang, Zhifa Cao, and Jingmin Guan
- Subjects
Male ,0301 basic medicine ,Carcinogenesis ,Immunology ,Active Transport, Cell Nucleus ,Protein Serine-Threonine Kinases ,medicine.disease_cause ,Article ,Culture Media, Serum-Free ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,Stress, Physiological ,Cell Line, Tumor ,medicine ,Humans ,Immunology and Allergy ,Amino Acid Sequence ,Solid Tumors ,Phosphorylation ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Cell Nucleus ,Hippo signaling pathway ,Cell growth ,Kinase ,Chemistry ,Tumor Suppressor Proteins ,HEK 293 cells ,Signal transducing adaptor protein ,YAP-Signaling Proteins ,Middle Aged ,Cell biology ,HEK293 Cells ,Phosphothreonine ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,Signal transduction ,Protein Binding ,Signal Transduction ,Transcription Factors - Abstract
An et al. identify a novel MST4-mediated YAP inactivation signaling pathway and demonstrate that the MST4–YAP axis is required to suppress gastric tumorigenesis in vivo., Hyperactivation of YAP has been commonly associated with tumorigenesis, and emerging evidence hints at multilayered Hippo-independent regulations of YAP. In this study, we identified a new MST4–YAP axis, which acts as a noncanonical Hippo signaling pathway that limits stress-induced YAP activation. MST4 kinase directly phosphorylated YAP at Thr83 to block its binding with importin α, therefore leading to YAP cytoplasmic retention and inactivation. Due to a consequential interplay between MST4-mediated YAP phospho-Thr83 signaling and the classical YAP phospho-Ser127 signaling, the phosphorylation level of YAP at Thr83 was correlated to that at Ser127. Mutation of T83E mimicking MST4-mediated alternative signaling restrained the activity of both wild-type YAP and its S127A mutant mimicking loss of classical Hippo signal. Depletion of MST4 in mice promoted gastric tumorigenesis with diminished Thr83 phosphorylation and hyperactivation of YAP. Moreover, loss of MST4–YAP signaling was associated with poor prognosis of human gastric cancer. Collectively, our study uncovered a noncanonical MST4–YAP signaling axis essential for suppressing gastric tumorigenesis., Graphical Abstract
- Published
- 2020