The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling

Giampietro, Costanza; Disanza, Andrea; Bravi, Luca; Barrios‐Rodiles, Miriam; Corada, Monica; Frittoli, Emanuela; Savorani, Cecilia; Lampugnani, Maria Grazia; Boggetti, Barbara; Niessen, Carien M.; Wrana, Jeff; Scita, Giorgio; Dejana, Elisabetta

doi:10.1083/jcb.201501089

Cited by 63 publications

(55 citation statements)

References 55 publications

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“…Recently, the Hippo transcriptional co-activator Yes-associated protein (YAP) was shown to mediate endothelial quiescence in concert with VE-cadherin through two separate pathways (Figure S11). [31, 44] In both pathways, phosphorylation results in inactivation of cytoplasmic YAP. In contrast, activated YAP translocates to the nucleus, where it induces expression of genes involved in angiogenic sprouting and vascular remodeling.…”

Section: Resultsmentioning

confidence: 99%

YAP-dependent mechanotransduction is required for proliferation and migration on native-like substrate topography

et al. 2017

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Native vascular extracellular matrices (vECM) consist of elastic fibers that impart varied topographical properties, yet most in vitro models designed to study the effects of topography on cell behavior are not representative of native architecture. Here, we engineer an electrospun elastin-like protein (ELP) system with independently tunable, vECM-mimetic topography and demonstrate that increasing topographical variation causes loss of endothelial cell-cell junction organization. This loss of VE-cadherin signaling and increased cytoskeletal contractility on more topographically varied ELP substrates in turn promote YAP activation and nuclear translocation, resulting in significantly increased endothelial cell migration and proliferation. Our findings identify YAP as a required signaling factor through which fibrous substrate topography influences cell behavior and highlights topography as a key design parameter for engineered biomaterials.

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Section: Resultsmentioning

confidence: 99%

YAP-dependent mechanotransduction is required for proliferation and migration on native-like substrate topography

et al. 2017

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“…However, the function and junctional recruitment of YAP tightly depend on VE-cadherin-based adhesion and are modulated by the tension-raising permeability agonist thrombin [102]. Moreover, the actin remodeling protein EGF receptor kinase substrate 8 (EPS8) has recently been shown to regulate the interaction of YAP with the VE-cadherin complex and to control endothelial permeability in vivo [103]. Recruitment of EPS8 to cell–cell junctions occurs via binding with α-catenin and is particularly prominent during junction remodeling in subconfluent endothelial monolayers.…”

Section: Intracellular Mechanotransductionmentioning

confidence: 99%

“…EPS8 binding competes with the interaction of YAP to the VE-cadherin complex and regulates VE-cadherin turnover. Upon adherens junction maturation, EPS8 dissociates from the VE-cadherin complex, and PI3K-mediated phosphorylation of YAP promotes its recruitment to cell–cell junctions and renders YAP transcriptionally inactive [103]. As mentioned before, force applied on cell–cell junctions activates PI3K, and therefore, this molecular event may provide a link between junctional mechanotransduction and transcription in maintenance of endothelial integrity.…”

Section: Intracellular Mechanotransductionmentioning

confidence: 99%

Cell–cell junctional mechanotransduction in endothelial remodeling

Dorland

Huveneers

2016

Cell. Mol. Life Sci.

135

142

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The vasculature is one of the most dynamic tissues that encounter numerous mechanical cues derived from pulsatile blood flow, blood pressure, activity of smooth muscle cells in the vessel wall, and transmigration of immune cells. The inner layer of blood and lymphatic vessels is covered by the endothelium, a monolayer of cells which separates blood from tissue, an important function that it fulfills even under the dynamic circumstances of the vascular microenvironment. In addition, remodeling of the endothelial barrier during angiogenesis and trafficking of immune cells is achieved by specific modulation of cell–cell adhesion structures between the endothelial cells. In recent years, there have been many new discoveries in the field of cellular mechanotransduction which controls the formation and destabilization of the vascular barrier. Force-induced adaptation at endothelial cell–cell adhesion structures is a crucial node in these processes that challenge the vascular barrier. One of the key examples of a force-induced molecular event is the recruitment of vinculin to the VE-cadherin complex upon pulling forces at cell–cell junctions. Here, we highlight recent advances in the current understanding of mechanotransduction responses at, and derived from, endothelial cell–cell junctions. We further discuss their importance for vascular barrier function and remodeling in development, inflammation, and vascular disease.

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“…Phosphorylated YAP level is density‐dependently increased in ECs, caused by activation of VE–cadherin‐mediated cell junctional complex and PI3K/Akt signalling, and results in decreased YAP activity (Choi et al, ). Similarly, the actin‐binding protein EPS8 associates with VE‐cadherin organization to promote YAP nuclear translocation and transcriptional activity (Giampietro et al, ). As a result, YAP deficiency leads to defective tubular network formation of ECs on Matrigel and suppresses sprouting from EC‐coated beads in fibrin gel, which is mediated by attenuating the expression of angiopoietin‐2 (Choi et al, ).…”

Section: Hippo/yap Pathway and Angiogenesismentioning

confidence: 99%

The role of Hippo/yes‐associated protein signalling in vascular remodelling associated with cardiovascular disease

Bao

Meng

et al. 2017

British J Pharmacology

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The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling

Abstract: EPS8, a regulator of actin dynamics, is a novel component of the adherens junction complex of endothelial cells and acts as the key protein through which VE-cadherin controls Yap transcriptional activity both in vitro and in vivo.

Cited by 63 publications

References 55 publications

YAP-dependent mechanotransduction is required for proliferation and migration on native-like substrate topography

YAP-dependent mechanotransduction is required for proliferation and migration on native-like substrate topography

Cell–cell junctional mechanotransduction in endothelial remodeling

The role of Hippo/yes‐associated protein signalling in vascular remodelling associated with cardiovascular disease

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