Abstract
The Hippo-YAP signaling pathway is a critical regulator of proliferation, apoptosis, and cell fate. The main downstream effector of this pathway, YAP, has been shown to be misregulated in human cancer and has emerged as an attractive target for therapeutics. A significant insufficiency in our understanding of the pathway is the identity of transcriptional targets of YAP that drive its potent growth phenotypes. Here, using liver cancer as a model, we identify NUAK2 as an essential mediator of YAP-driven hepatomegaly and tumorigenesis in vivo. By evaluating several human cancer cell lines we determine that NUAK2 is selectively required for YAP-driven growth. Mechanistically, we found that NUAK2 participates in a feedback loop to maximize YAP activity via promotion of actin polymerization and myosin activity. Additionally, pharmacological inactivation of NUAK2 suppresses YAP-dependent cancer cell proliferation and liver overgrowth. Importantly, our work here identifies a specific, potent, and actionable target for YAP-driven malignancies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Actins / metabolism
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antineoplastic Agents / pharmacology
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Benzodiazepinones / pharmacology
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Carcinogenesis / drug effects
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Carcinogenesis / genetics*
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / genetics*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Feedback, Physiological
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Gene Expression Regulation, Neoplastic*
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Humans
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Liver Neoplasms / drug therapy
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Liver Neoplasms / genetics*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Mice
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Mice, Nude
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Myosins / genetics
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Myosins / metabolism
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction
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Xenograft Model Antitumor Assays
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YAP-Signaling Proteins
Substances
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Actins
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Benzodiazepinones
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Cell Cycle Proteins
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Phosphoproteins
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YAP-Signaling Proteins
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Yap1 protein, mouse
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Protein Serine-Threonine Kinases
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SNARK protein, mouse
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Myosins