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      Tankyrase Inhibitor Sensitizes Lung Cancer Cells to Endothelial Growth Factor Receptor (EGFR) Inhibition via Stabilizing Angiomotins and Inhibiting YAP Signaling.

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          Abstract

          YAP signaling pathway plays critical roles in tissue homeostasis, and aberrant activation of YAP signaling has been implicated in cancers. To identify tractable targets of YAP pathway, we have performed a pathway-based pooled CRISPR screen and identified tankyrase and its associated E3 ligase RNF146 as positive regulators of YAP signaling. Genetic ablation or pharmacological inhibition of tankyrase prominently suppresses YAP activity and YAP target gene expression. Using a proteomic approach, we have identified angiomotin family proteins, which are known negative regulators of YAP signaling, as novel tankyrase substrates. Inhibition of tankyrase or depletion of RNF146 stabilizes angiomotins. Angiomotins physically interact with tankyrase through a highly conserved motif at their N terminus, and mutation of this motif leads to their stabilization. Tankyrase inhibitor-induced stabilization of angiomotins reduces YAP nuclear translocation and decreases downstream YAP signaling. We have further shown that knock-out of YAP sensitizes non-small cell lung cancer to EGFR inhibitor Erlotinib. Tankyrase inhibitor, but not porcupine inhibitor, which blocks Wnt secretion, enhances growth inhibitory activity of Erlotinib. This activity is mediated by YAP inhibition and not Wnt/β-catenin inhibition. Our data suggest that tankyrase inhibition could serve as a novel strategy to suppress YAP signaling for combinatorial targeted therapy.

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          Author and article information

          Journal
          J. Biol. Chem.
          The Journal of biological chemistry
          American Society for Biochemistry & Molecular Biology (ASBMB)
          1083-351X
          0021-9258
          July 15 2016
          : 291
          : 29
          Affiliations
          [1 ] From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
          [2 ] Department of Biological Structure, University of Washington, Seattle, Washington 98195.
          [3 ] From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and feng.cong@novartis.com.
          Article
          M116.722967
          10.1074/jbc.M116.722967
          4946938
          27231341
          4088075f-1333-44a7-8435-d6676e7db656
          History

          CRISPR/Cas,drug resistance,functional genomics,protein degradation,signal transduction,yes-associated protein (YAP)

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