Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

Choi, Hyun Jung; Zhang, Haiying; Park, Hongryeol; Choi, Kyu Sung; Lee, Heon Woo; Agrawal, Vijayendra; Kim, Young Myeong; Kwon, Young Guen

doi:10.1038/ncomms7943

Cited by 215 publications

(264 citation statements)

References 47 publications

Supporting

Mentioning

236

Contrasting

Order By: Relevance

“…2, panel C) and, concurrently, a YAP nuclear accumulation, which was already reported. 29 This result is consistent with the previously demonstrated competition between EPS8 and YAP for junctional localization. 20 Our findings add further knowledge to a number of recent reports, revealing that the co-transcriptional regulator, YAP, originally characterized as the molecular target of the size controlling Hippo pathway, 21 is a key transmitter of mechanical inputs in gene transcriptional programs.…”

Section: Eps8 As a Novel Component Of Endothelial Adherens Junctionssupporting

confidence: 92%

“…Finally, morphogenetic signals such as Wnt, Rho-GTPases, G-protein coupled receptors (GPCRs), PI(3)K-Akt signaling pathway and mevalonate metabolism modulate YAP phosphorylation and activity. 27,29 We showed that YAP associates with adherens junctions through a-catenin. This association specifically occurs in long confluent monolayers of ECs in vitro (Fig.…”

Section: Structure and Function Of Vascular Endothelial Adherens Juncmentioning

confidence: 99%

See 1 more Smart Citation

VE-cadherin complex plasticity: EPS8 and YAP play relay at adherens junctions

Giampietro

2016

Tissue Barriers

View full text Add to dashboard Cite

The vascular endothelium is a selective barrier that separates the organs from the circulating blood. The endothelium has a wide variety of functions controlled by cell-to-cell junctions and in particular by Vascular Endothelial cadherin (VE-cadherin) complexes. Recent research identified the epidermal growth factor receptor kinase substrate 8 (EPS8) and the co-transcriptional regulator yes-associated protein (YAP) as new components of the adherens junction complexes. The binding of these 2 proteins to VE-cadherin determines the formation of different specialized adhesive structures contributing to the dynamic control of vascular permeability. This commentary will summarize what is currently known about the role of EPS8 and YAP in the modification of molecular organization and intracellular signaling of adherens junction complexes, and their potential multiple effects on vascular homeostasis. Structure and function of vascular endothelial adherens junctionsThe vascular endothelium is a highly dynamic cell layer formed by endothelial cells (ECs), a heterogeneous cell population performing essential functions in physiological and pathological processes.1,2 ECs vary in their phenotypes and in protein and surface marker expression in different tissues.3 The heterogeneity of the ECs contributes to their functional diversity at various vascular sites. 4 The organization of the junctions also differs in composition and morphological features along the vascular tree, depending on the specific permeability requirements.1,5 Endothelial tissue integrity and the establishment of cell polarity, differentiation and survival are ensured by the formation of adhesive structures between adjacent ECs.Cell-to-cell interactions are regulated by dynamic structures allowing cohesion and plasticity of organs during morphogenesis, and in the adult life. In vascular ECs, junctional complexes maintain homeostasis of blood vessels, while retaining their capacity to reorganize during angiogenesis. Both adherens and tight junction complexes, connecting adjacent cells, are characterized by a high degree of plasticity. They can rapidly respond to extracellular environmental changes, such as pro-and anti-angiogenic, and inflammatory stimuli, shear stress and blood flow inducing substantial and reversible alterations of the endothelial barrier functions. The adherens junction protein VE-cadherin is a endothelial-specific adhesion molecule located at junctions of ECs and responsible for barrier architecture and function.6 VE-cadherin is a transmembrane protein that promotes homophilic interactions, forming a pericellular zipper-like structure along cell boundaries. The association of the C-terminus domain of VE-cadherin with cytoplasmic proteins is needed for its adhesive functions.7 Through its cytoplasmic tail, VEcadherin binds both cytoskeletal and signaling proteins, which in turn allow the anchoring of cadherin to the actin microfilaments and the activation of outside-in signaling. 5,8 The association with actin is required for the ...

show abstract

Section: Eps8 As a Novel Component Of Endothelial Adherens Junctionssupporting

confidence: 92%

Section: Structure and Function Of Vascular Endothelial Adherens Juncmentioning

confidence: 99%

VE-cadherin complex plasticity: EPS8 and YAP play relay at adherens junctions

Giampietro

2016

Tissue Barriers

View full text Add to dashboard Cite

show abstract

“…S7B), suggesting the flow regulation of YAP/TAZ activities does not solely depend on LATS kinases but also through the modulation of Rho-GTPase activities. In addition to the Hippo and Rho-GTPase pathways, other known mechanosensors, such as G protein-coupled receptors and integrins (23,24), and mechanotransduction pathways, including AMP-activated protein kinase, and VE-cadherinmediated phosphatidylinositol 3-kinase (PI3K)/AKT signaling (25,26), have been shown to modulate YAP/TAZ activities through phosphorylation. It would be worthwhile to further delineate the Hippo signaling cascade and the cross-talk between the flow-sensitive pathways that modulate YAP/TAZ activities.…”

Section: Discussionmentioning

confidence: 99%

Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis

Wang

Yeh

Nguyen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

354

352

View full text Add to dashboard Cite

The focal nature of atherosclerotic lesions suggests an important role of local hemodynamic environment. Recent studies have demonstrated significant roles of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in mediating mechanotransduction and vascular homeostasis. The objective of this study is to investigate the functional role of YAP/TAZ in the flow regulation of atheroprone endothelial phenotypes and the consequential development of atherosclerotic lesions. We found that exposure of cultured endothelial cells (ECs) to the atheroprone disturbed flow resulted in YAP/TAZ activation and translocation into EC nucleus to up-regulate the target genes, including cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), and ankyrin repeat domain 1 (ANKRD1). In contrast, the atheroprotective laminar flow suppressed YAP/TAZ activities. En face analysis of mouse arteries demonstrated an increased nuclear localization of YAP/TAZ and elevated levels of the target genes in the endothelium in atheroprone areas compared with athero-protective areas. YAP/TAZ knockdown significantly attenuated the disturbed flow induction of EC proliferative and proinflammatory phenotypes, whereas overexpression of constitutively active YAP was sufficient to promote EC proliferation and inflammation. In addition, treatment with statin, an antiatherosclerotic drug, inhibited YAP/TAZ activities to diminish the disturbed flow-induced proliferation and inflammation. In vivo blockade of YAP/TAZ translation by morpholino oligos significantly reduced endothelial inflammation and the size of atherosclerotic lesions. Our results demonstrate a critical role of the activation of YAP/TAZ by disturbed flow in promoting atheroprone phenotypes and atherosclerotic lesion development. Therefore, inhibition of YAP/TAZ activation is a promising athero-protective therapeutic strategy.atherogenesis | disturbed flow | endothelial cells | mechanotransduction

show abstract

“…This reflects the potentially detrimental consequences of a deficiency or an excess of blood vessels. The Hippo signaling pathway has been implicated in vascular development (36)(37)(38) but the underlying mechanisms have not been fully described. In this study, we found that the cytoplasmically localized phospho-YAP, which is not involved in transcription, plays an important role in promoting cell migration via activating CDC42.…”

Section: Discussionmentioning

confidence: 99%

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

Sakabe

Fan

Odaka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

166

157

View full text Add to dashboard Cite

Angiogenesis and vascular remodeling are essential for the establishment of vascular networks during organogenesis. Here we show that the Hippo signaling pathway effectors YAP and TAZ are required, in a gene dosage-dependent manner, for the proliferation and migration of vascular endothelial cells (ECs) during retinal angiogenesis. Intriguingly, nuclear translocation of YAP and TAZ induced by Lats1/2-deletion blocked endothelial migration and phenocopied Yap/Taz-deficient mutants. Furthermore, overexpression of a cytoplasmic form of YAP (YAPS127D) partially rescued the migration defects caused by loss of YAP and TAZ function. Finally, we found that cytoplasmic YAP positively regulated the activity of the small GTPase CDC42, deletion of which caused severe defects in endothelial migration. These findings uncover a previously unrecognized role of cytoplasmic YAP/TAZ in promoting cell migration by activating CDC42 and provide insight into how Hippo signaling in ECs regulates angiogenesis.A ngiogenesis is a process of growth and remodeling in vascular networks that is essential for normal development. In adulthood, angiogenesis is activated as a reparative process, for example, during wound healing (1, 2). Aberrantly regulated angiogenesis can also be a component of disease (3) and can play a key role in tumor growth and metastasis (4), inflammatory diseases (5), diabetic retinopathy, and retinopathy of prematurity (6).Retinal angiogenesis in mice begins at postnatal day 0 (P0). The retinal vasculature initiates its expansion from the optic nerve head and migrates outwards along a preexisting network of astrocytes (7,8). This results in the formation of the superficial vascular plexus within the retinal ganglion cell layer during the first 8 d (9, 10). Endothelial cells (ECs) then migrate along nerve fibers to establish deep and intermediate vascular layers (9,11). Cell proliferation and migration are essential for angiogenesis and these cell responses are regulated by many different signaling pathways, including the VEGF, Notch, Wnt, FGF, BMP, and integrin signaling responses (9, 12-16). VEGFA and CDC42 are known to regulate extension of the angiogenic front and filopodia formation in angiogenic tip cells (2,17,18).The Hippo signaling pathway is an evolutionarily conserved, pivotal regulator of cell proliferation and organogenesis. YAP and TAZ are key components of the Hippo signaling pathway and function as transcription cofactors that regulate downstream gene expression via association with DNA binding proteins such as 20). Loss of Hippo signaling can drive the expression of genes that regulate cell proliferation and survival (diap1, bantam, cyclin E, and E2F1), the Hippo pathway (Kibra, Crb, and Fj), and cell-cell interaction (E-Cadherin, Serrate, Wingless, and Vein) (20). The activity of YAP and TAZ is regulated by the LATS1 and LATS2 kinases. These kinases phosphorylate YAP and TAZ, thus preventing their nuclear translocation and regulating transcriptional activity. Although the function of YAP and TAZ in the ...

show abstract

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

Cited by 215 publications

References 47 publications

VE-cadherin complex plasticity: EPS8 and YAP play relay at adherens junctions

VE-cadherin complex plasticity: EPS8 and YAP play relay at adherens junctions

Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

Contact Info

Product

Resources

About