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

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.

A cooperative response to endocardial NOTCH signaling stimulation regulates transcriptional activity during cardiac valve development and disease

“…Based on this finding, we sought evidence for cooperation between the Notch and Hippo pathways in the embryonic endocardium. Genes targeted by the Hippo pathway downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) were identified in available transcriptional data from human umbilical endothelial cells (HUVEC) transduced with the transcriptionally active forms YAP S127A and TAZ S89A 43 . We then assessed the representation of these YAP/TAZ endothelial target genes among the MEEC DEGs identified in the MEEC–OP9 co-culture model (clusters C1-C4).…”

Hippo effector, Yorkie, is a Tumor Suppressor in SelectDrosophilaSquamous Epithelia

“…This scenario appears reminiscent of disparate outcomes of loss of YAP/TAZ in a diverse type of flattened and mechanostrained human cells. For instance, YAP/TAZ loss-induced lung SCC (Huang et al, 2017), alveolar cysts in mammalian lungs (Mahoney et al, 2014; van Soldt et al, 2019), loss of differentiation of flattened retinal pigment epithelium (Kim et al, 2016), or arrested vasculogenesis when lost in blood vessel endothelial cells (Ong et al, 2022). Therefore, we asked if SEs lining the lumens of other tubular organs in Drosophila are susceptible to loss of Yki signaling, like that of MAG.…”

Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2

“…Endothelium-specific loss of YAP/TAZ has been shown to result in impaired tumor and developmental angiogenesis [24][25][26]29,51 , whereas endothelium-specific overexpression of YAP or TAZ increased angiogenesis 28,29,54 . Consistent with a general role of FAT1 in the negative regulation of endothelial YAP/TAZ, we found that loss of FAT1 resulting in YAP/TAZ activation increased endothelial cell proliferation during postnatal retinal angiogenesis as well as in tumor angiogenesis.…”