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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Biosensing Techniques*
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Blotting, Western
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Female
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HEK293 Cells
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Humans
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Immunohistochemistry
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Mutagenesis, Site-Directed
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptors, Vascular Endothelial Growth Factor / genetics
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Phosphoproteins
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Transcription Factors
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Tumor Suppressor Proteins
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LATS2 protein, human
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Receptors, Vascular Endothelial Growth Factor
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Protein Serine-Threonine Kinases