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

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. Nicol and X. Yang ()
Additional contact information
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

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03278-w

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