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

Taha AzadDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada, K7L3N6Helena J. Janse van RensburgDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada, K7L3N6Elizabeth D. LightbodyDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada, K7L3N6Bertrand NeveuDepartment of Surgery (Urology), CHU de Québec-Université Laval Research Center, Laval University, Quebec, Ontario, Canada, G1V 0A6Audrey ChampagneDepartment of Surgery (Urology), CHU de Québec-Université Laval Research Center, Laval University, Quebec, Ontario, Canada, G1V 0A6Abdi GhaffariDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada, K7L3N6Vanessa R. KayDepartment of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada, K7L 3N6Y HaoDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada, K7L3N6He ShenDepartment of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USABenjamin YeungDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada, K7L3N6B. Anne CroyDepartment of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada, K7L 3N6Kun‐Liang GuanDepartment of Pharmacology, University of California at San Diego, La Jolla, CA, 92093, USAFrédéric PouliotDepartment of Surgery (Urology), CHU de Québec-Université Laval Research Center, Laval University, Quebec, Ontario, Canada, G1V 0A6J. ZhangDepartment of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USAChristopher J.B. NicolDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada, K7L3N6Xiaolong YangDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada, K7L3N6. [email protected]

2018en

ABI

Annotatsiya

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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DOI: 10.1038/s41467-018-03278-w

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