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A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth

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Item Type:Article
Title:A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth
Creators Name:Ong, Y.T. and Andrade, J. and Armbruster, M. and Shi, C. and Castro, M. and Costa, A.S.H. and Sugino, T. and Eelen, G. and Zimmermann, B. and Wilhelm, K. and Lim, J. and Watanabe, S. and Guenther, S. and Schneider, A. and Zanconato, F. and Kaulich, M. and Pan, D. and Braun, T. and Gerhardt, H. and Efeyan, A. and Carmeliet, P. and Piccolo, S. and Grosso, A.R. and Potente, M.
Abstract:Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs-elicited by the loss of Rag GTPases-inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
Keywords:Angiogenesis, HIPPO Signalling, Metabolism, TOR Signalling, Animals, Mice
Source:Nature Metabolism
ISSN:2522-5812
Publisher:Nature Publishing Group
Volume:4
Number:6
Page Range:672–682
Date:June 2022
Official Publication:https://doi.org/10.1038/s42255-022-00584-y
PubMed:View item in PubMed

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