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; Wrana, Jeff; Scita, Giorgio; Dejana, Elisabetta

doi:10.1085/jgp.1472oia9

Cited by 10 publications

(26 citation statements)

References 31 publications

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“…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. 22 Indeed, multiple signaling pathways integrating biophysical and biochemical cues, converge to regulate the activity of YAP.…”

Section: Eps8 As a Novel Component Of Endothelial Adherens Junctionssupporting

confidence: 79%

“…17 All these reports demonstrate the importance of the receptor function of VE-cadherin, regulating many intracellular signaling pathways triggering gene transcription, controlling endothelial cell fate and contributing to vascular homeostasis. 16,18,19 We recently identified 2 novel components of the adherens junction complex in ECs 20 : the co-transcriptional regulator yes-associated protein (YAP) [21][22][23] and the epidermal growth factor receptor kinase substrate 8 (EPS8). [24][25][26] YAP as a novel component of endothelial adherens junctions YAP plays a crucial role in organ size control, cell proliferation and in the amplification of tissue-specific progenitor cells during tissue renewal and regeneration.…”

Section: Structure and Function Of Vascular Endothelial Adherens Juncmentioning

confidence: 99%

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

Giampietro

2016

Tissue Barriers

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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 ...

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Section: Eps8 As a Novel Component Of Endothelial Adherens Junctionssupporting

confidence: 79%

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

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“…40. Endothelial cells were isolated from lungs of wild-type adult mice and cultured as previously described (29). Starving medium was MCDB 131 (Invitrogen) with 1% BSA (EuroClone), 2 mM glutamine, 100 U/liter penicillin/streptomycin, and 1 mM sodium pyruvate.…”

Section: Methodsmentioning

confidence: 99%

“…Internal couplings usually play a key role in avalanche statistics (23,(25)(26)(27). To understand this point in our context, we assess the role of cell-cell interactions performing the same cell migration assay knocking down VE-cadherin in mouse endothelial cells (29). VE-cadherin is an endothelial-specific cadherin molecule located at adherent junctions which regulates adhesion between adjacent endothelial cells.…”

Section: Significancementioning

confidence: 99%

Bursts of activity in collective cell migration

Chepizhko

Giampietro

Mastrapasqua

et al. 2016

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

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Dense monolayers of living cells display intriguing relaxation dynamics, reminiscent of soft and glassy materials close to the jamming transition, and migrate collectively when space is available, as in wound healing or in cancer invasion. Here we show that collective cell migration occurs in bursts that are similar to those recorded in the propagation of cracks, fluid fronts in porous media, and ferromagnetic domain walls. In analogy with these systems, the distribution of activity bursts displays scaling laws that are universal in different cell types and for cells moving on different substrates. The main features of the invasion dynamics are quantitatively captured by a model of interacting active particles moving in a disordered landscape. Our results illustrate that collective motion of living cells is analogous to the corresponding dynamics in driven, but inanimate, systems.collective cell migration | avalanches | universality | vascular endothelial cadherin | collagen substrate C ollective cell movement depends on intracellular biological mechanisms as well as environmental cues due to the extracellular matrix (1-5), mainly composed of collagen which is organized in hierarchical structures, such as fibrils and fibers. The mechanical properties of collagen fibril networks are essential to offer little resistance and high sensitivity to small deformations, allowing easy local remodeling and strong strain stiffening needed to ensure cell and tissue integrity (6). Wound healing is a typical biological assay to study collective migration of cells under controlled conditions in vitro and is a prototypical experimental method to study active matter (7-10). Experiments performed on soluble collagen (11) or other gels (12), micropatterned (13, 14) and deformable substrates (1) show that cell migration is guided by the substrate structure and stiffness (5,15,16).It has been argued that collective migration properties arise from stresses transmitted between neighboring cells (1) giving rise to longranged stress waves in the monolayer (17,18). Hence the dynamics of an invading cell sheet is ruled by a combination of long-range internal stresses and interactions with the substrate, suggesting an analogy with driven elastic systems moving in a disordered medium such as cracks lines (19,20), imbibition fronts (21), or ferromagnetic domain walls (22). The scaling laws in these systems are usually associated with a depinning critical point that has been widely studied by simple models for interface dynamics. Thanks to a combination of numerical simulations (23, 24) and renormalization group theory (23,(25)(26)(27), we now have a detailed picture of the nonequilibrium phase transitions and universality classes in these systems. Here we substantiate the analogy between collective cell migration and depinning by revealing and characterizing widely distributed bursts of activity in the collective migration of different types of cells (human cancer cells and epithelial cells, mouse endothelial cells) over different substrates ...

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“…Previous studies demonstrated Hippo/YAP signaling is critical in regulating EC survival, proliferation and migration [9,10]. Activation of YAP caused by activation of VE-cadherin, PI3K/Akt signaling, and actin-binding protein EPS8 results in tubular network formation [7,11].…”

Section: Introductionmentioning

confidence: 98%

YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis Through Activating Yap Signaling in Vascular Endothelial Cells

Yoshida

Song

Yao

et al. 2020

Preprint

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Background:The YAP signaling pathway is altered and implicated as oncogenic in human mammary cancers.However, roles of YAP signaling that regulate the breast tumor angiogenesis have remained elusive. Tumor angiogenesis is coordinated by the activation of both cancer cells and vascular endothelial cells. Whether the YAP signalingpathway can regulate the intercellular interaction between cancer cells and endothelial cellsis essentially unknown.Results: We showed here that conditioned media from YAP overexpressed breast cancer cells (CM-YAP+) could promote angiogenesis, accompanied byincreased tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs). Down regulation of YAP in HUVECs reversed CM-YAP+ induced angiogenesis.CM-YAP+ time-dependently activated YAP inHUVECs by dephosphorylating YAP and increasing nuclear translocation.We also identified that both G13-RhoA and PI3K/Akt signaling pathway were necessary for CM-YAP+ induced activation of YAP.Besides, connective tissue growth factor (CTGF) and angiopoietin-2 (ANG-2)actedas down-stream of YAP in HUVECs to promote angiogenesis.In addition, subcutaneous tumors nude mice model demonstrated that tumors overexpressed YAP revealed moreneovascularization in vivo.Conclusions: YAP-YAP interaction between breastcancer cells and endothelial cellscould promote tumor angiogenesis, supporting that YAP is a potential marker and target fordeveloping novel therapeutic strategies against breast cancer.

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

Cited by 10 publications

References 31 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

Bursts of activity in collective cell migration

YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis Through Activating Yap Signaling in Vascular Endothelial Cells

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