Endothelial YAP/TAZ (YAP is also known as YAP1, and TAZ as WWTR1) signaling is crucial for sprouting angiogenesis and vascular homeostasis. However, the underlying molecular mechanisms that explain how YAP/TAZ control the vasculature remain unclear. This study reveals that the focal adhesion protein deleted-in-liver-cancer 1 (DLC1) is a direct transcriptional target of the activated YAP/TAZ-TEAD complex. We find that substrate stiffening and VEGF stimuli promote expression of DLC1 in endothelial cells. In turn, DLC1 expression levels are YAP and TAZ dependent, and constitutive activation of YAP is sufficient to drive DLC1 expression. DLC1 is needed to limit 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, ectopic expression of DLC1 is sufficient to restore migration and angiogenic sprouting in YAP-depleted cells. Together, these findings point towards a crucial and prominent role for DLC1 in YAP/TAZ-driven endothelial adhesion remodeling and collective migration during angiogenesis.This article has an associated First Person interview with the first author of the paper.
Keywords: Adhesion; Angiogenesis; Endothelium; Integrin; Mechanotransduction; YAP.
© 2020. Published by The Company of Biologists Ltd.
Conflict of interest statement
Competing interestsThe authors declare no competing or financial interests.
Zebrafish mutants and TEAD reporters reveal essential functions for Yap and Taz in posterior cardinal vein development.Sci Rep. 2018 Jul 5;8(1):10189. doi: 10.1038/s41598-018-27657-x. Sci Rep. 2018. PMID: 29976931 Free PMC article.
YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy.Bioessays. 2020 Mar 4:e1900162. doi: 10.1002/bies.201900162. Online ahead of print. Bioessays. 2020. PMID: 32128850
Role of Hippo Pathway-YAP/TAZ Signaling in Angiogenesis.Front Cell Dev Biol. 2019 Apr 10;7:49. doi: 10.3389/fcell.2019.00049. eCollection 2019. Front Cell Dev Biol. 2019. PMID: 31024911 Free PMC article. Review.
TNF-α-Induced YAP/TAZ Activity Mediates Leukocyte-Endothelial Adhesion by Regulating VCAM1 Expression in Endothelial Cells.Int J Mol Sci. 2018 Nov 1;19(11):3428. doi: 10.3390/ijms19113428. Int J Mol Sci. 2018. PMID: 30388809 Free PMC article.
Evolution of mechanotransduction via YAP/TAZ in animal epithelia.Curr Opin Cell Biol. 2018 Apr;51:117-123. doi: 10.1016/j.ceb.2018.02.003. Epub 2018 Feb 21. Curr Opin Cell Biol. 2018. PMID: 29477107 Review.