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

  • Author(s): Azad, T;
  • Janse van Rensburg, HJ;
  • Lightbody, ED;
  • Neveu, B;
  • Champagne, A;
  • Ghaffari, A;
  • Kay, VR;
  • Hao, Y;
  • Shen, H;
  • Yeung, B;
  • Croy, BA;
  • Guan, KL;
  • Pouliot, F;
  • Zhang, J;
  • Nicol, CJB;
  • Yang, X
  • et al.
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.

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