A LATS biosensor screen identiﬁes VEGFR as a
regulator of the Hippo pathway in angiogenesis
, H.J. Janse van Rensburg
, E.D. Lightbody
, B. Neveu
, A. Champagne
, A. Ghaffari
, V.R. Kay
, H. Shen
, B. Yeung
, B.A. Croy
, K.L. Guan
, F. Pouliot
, J. Zhang
, C.J.B. Nicol
& X. Yang
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.
Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada K7L3N6.
Department of Surgery (Urology), CHU de
Québec-Université Laval Research Center, Laval University, Quebec, Ontario, Canada G1V 0A6.
Department of Biomedical and Molecular Sciences, Queen’s
University, Kingston, Ontario, Canada K7L 3N6.
Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA. Correspondence and requests for materials should be
addressed to X.Y. (email: email@example.com)