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A LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis

Author

Listed:
  • T. Azad

    (Queen’s University)

  • H. J. Janse van Rensburg

    (Queen’s University)

  • E. D. Lightbody

    (Queen’s University)

  • B. Neveu

    (Laval University)

  • A. Champagne

    (Laval University)

  • A. Ghaffari

    (Queen’s University)

  • V. R. Kay

    (Queen’s University)

  • Y. Hao

    (Queen’s University)

  • H. Shen

    (Roswell Park Cancer Institute)

  • B. Yeung

    (Queen’s University)

  • B. A. Croy

    (Queen’s University)

  • K. L. Guan

    (University of California at San Diego)

  • F. Pouliot

    (Laval University)

  • J. Zhang

    (Roswell Park Cancer Institute)

  • C. J. B. Nicol

    (Queen’s University)

  • X. Yang

    (Queen’s University)

Abstract

The Hippo pathway is a central regulator of tissue development and homeostasis, and has been reported to have a role during vascular development. Here we develop a bioluminescence-based biosensor that monitors the activity of the Hippo core component LATS kinase. Using this biosensor and a library of small molecule kinase inhibitors, we perform a screen for kinases modulating LATS activity and identify VEGFR as an upstream regulator of the Hippo pathway. We find that VEGFR activation by VEGF triggers PI3K/MAPK signaling, which subsequently inhibits LATS and activates the Hippo effectors YAP and TAZ. We further show that the Hippo pathway is a critical mediator of VEGF-induced angiogenesis and tumor vasculogenic mimicry. Thus, our work offers a biosensor tool for the study of the Hippo pathway and suggests a role for Hippo signaling in regulating blood vessel formation in physiological and pathological settings.

Suggested Citation

  • T. Azad & H. J. Janse van Rensburg & E. D. Lightbody & B. Neveu & A. Champagne & A. Ghaffari & V. R. Kay & Y. Hao & H. Shen & B. Yeung & B. A. Croy & K. L. Guan & F. Pouliot & J. Zhang & C. J. B. Nico, 2018. "A LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03278-w
    DOI: 10.1038/s41467-018-03278-w
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    Cited by:

    1. Carmen Oi Ning Leung & Yang Yang & Rainbow Wing Hei Leung & Karl Kam Hei So & Hai Jun Guo & Martina Mang Leng Lei & Gregory Kenneth Muliawan & Yuan Gao & Qian Qian Yu & Jing Ping Yun & Stephanie Ma & , 2023. "Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Rui Li & Jingchen Shao & Young-June Jin & Haruya Kawase & Yu Ting Ong & Kerstin Troidl & Qi Quan & Lei Wang & Remy Bonnavion & Astrid Wietelmann & Francoise Helmbacher & Michael Potente & Johannes Gra, 2023. "Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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