DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis

van der Stoel, M.; Schimmel, L.; Nawaz, K.; van Stalborch, A.-M.; de Haan, A.; Klaus-Bergmann, A.; Valent, E. T.; Koenis, D. S.; van Nieuw Amerongen, G. P.; de Vries, C. J.; de Waard, V.; Gloerich, M.; van Buul, J. D.; Huveneers, S.

doi:10.1101/755389

bioRxiv · 10.1101/755389

DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis

van der Stoel, M.·Schimmel, L.·Nawaz, K.·van Stalborch, A.-M.·de Haan, A.·Klaus-Bergmann, A.·Valent, E. T.·Koenis, D. S.·van Nieuw Amerongen, G. P.·de Vries, C. J.·de Waard, V.·Gloerich, M.·van Buul, J. D.·Huveneers, S.

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Abstract

YAP/TAZ signaling is crucial for sprouting angiogenesis and vascular homeostasis through the regulation of endothelial remodeling. Thus far the underlying molecular mechanisms that explain how YAP/TAZ control the vasculature remain unclear. We here identify Deleted-in-Liver-Cancer-1 (DLC1) as a direct transcriptional target of the activated YAP/TAZ-TEAD complex in the endothelium. Substrate stiffening and VEGF stimuli promote the endothelial expression of DLC1. DLC1 expression is dependent on the presence of YAP and TAZ, and constitutive activation of YAP efficiently promotes expression of DLC1. We show that DLC1 limits F-actin fiber formation, integrin-based focal adhesion lifetime and integrin-mediated traction forces. Depletion of endothelial DLC1 strongly perturbs cell polarization in directed collective migration and inhibits the formation of angiogenic sprouts. Importantly, the inability of YAP-depleted endothelial cells to collectively migrate and form angiogenic sprouts can be rescued by ectopic expression of DLC1. Together, these findings reveal that DLC1 fills a hitherto missing link between YAP/TAZ signaling and endothelial dynamics during angiogenesis.

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van der Stoel, M., Schimmel, L., Nawaz, K., van Stalborch, A.-M., de Haan, A., Klaus-Bergmann, A., Valent, E. T., Koenis, D. S., van Nieuw Amerongen, G. P., de Vries, C. J., de Waard, V., Gloerich, M., van Buul, J. D., Huveneers, S.. 2019-09-02. DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis. https://doi.org/10.1101/755389

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