Author response: YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development

Neto, Filipa; Klaus-Bergmann, Alexandra; Ong, Yu Ting; Alt, Silvanus; Vion, Anne-Clémence; Szymborska, Anna; Carvalho, Joana Rita; Hollfinger, Irene; Bartels-Klein, Eireen; Franco, Cláudio A.; Potente, Michael; Gerhardt, Holger

doi:10.7554/elife.31037.043

Cited by 4 publications

(1 citation statement)

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“…Increased cytoplasmic distribution and enhanced phosphorylation of YAP at Ser127 leading to its proteosomal degradation are observed after agrin knockdown through siRNA or shRNA in liver or breast cancer cells, respectively (18). In ECs, YAP/Taz plays an important role in the regulation of EC development (19), angiogenesis and endothelial barrier maturation (20). Therefore, we sought to understand whether agrin is required for endothelial activation of YAP/Taz in vivo by analyzing the expression and phosphorylation levels of nuclear and cytoplasmic YAP and Taz in CD31 + ECs purified from the skeletal muscle of EC-agrn fl/fl and EC-agrn +/+ mice for western blotting, respectively (Figure 6A).…”

Section: Endothelial Agrin Is Dispensable For Tumor Angiogenesis During Tumor Growth and Metastasismentioning

confidence: 99%

Endothelial Agrin Is Dispensable for Normal and Tumor Angiogenesis

Chung

et al. 2022

Front. Cardiovasc. Med.

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Recently, the extracellular matrix protein agrin has been reported to promote tumor angiogenesis that supports tumorigenesis and metastasis; however, there is a lack of in vivo genetic evidence to prove whether agrin derived from the tumors or endothelial cells (ECs) systemically should be the therapeutic target. To date, the physiological role of endothelial agrin has also not been investigated. In the EC-specific agrin knockout mice, we observed normal endothelial and haematopoietic cell development during embryogenesis. Moreover, these mice develop normal vascular barrier integrity and vasoreactivity at the adult stage. Importantly, the growth of localized or metastatic cancer cells was not affected after implantation into endothelial agrin depleted mice. Mechanistically, agrin did not regulate endothelial ERK1/2, YAP or p53 activation in vivo that is central to support endothelial proliferation, survival and invasion. Cumulatively, our findings may suggest that agrin could play a redundant role in endothelial development during physiological and tumor angiogenesis. Targeting the endothelial derived agrin might not be effective in inhibiting tumor angiogenesis.

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Section: Endothelial Agrin Is Dispensable For Tumor Angiogenesis During Tumor Growth and Metastasismentioning

confidence: 99%

Endothelial Agrin Is Dispensable for Normal and Tumor Angiogenesis

Chung

et al. 2022

Front. Cardiovasc. Med.

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The Hippo Pathway, YAP/TAZ, and the Plasma Membrane

Rausch

Hansen

2020

Trends in Cell Biology

180

154

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The plasma membrane allows the cell to sense and adapt to changes in the extracellular environment by relaying external inputs via intracellular signaling networks. One central cellular signaling pathway is the Hippo pathway, which regulates homeostasis and plays chief roles in carcinogenesis and regenerative processes. Recent studies have found that mechanical stimuli and diffusible chemical components can regulate the Hippo pathway primarily through receptors embedded in the plasma membrane. Morphologically defined structures within the plasma membrane, such as cellular junctions, focal adhesions, primary cilia, caveolae, clathrin-coated pits, and plaques play additional key roles. Here, we discuss recent evidence highlighting the importance of these specialized plasma membrane domains in cellular feedback via the Hippo pathway. Cellular Regulation by the Hippo PathwayThe plasma membrane is essential for cell integrity and serves as an interface to sense and respond to changes in the extracellular environment [1]. A large variety of plasma membrane domains, such as, adherens and tight junctions (see Glossary), focal adhesions (FAs), clathrin-coated pits (CCPs) or plaques, caveolae, and primary cilia [2-8], allow the cell to dynamically relay chemical and mechanical stimuli, which are translated into direct cellular responses. The plasma membrane as a whole, but FAs in particular, strongly interacts with the extracellular matrix (ECM) [9]. The ECM is a dynamic noncellular matrix surrounding cells and tissues that acts as a scaffold for cell anchorage and mechanotransduction [9]. The signals perceived by plasma membrane elements are integrated and transmitted by a variety of signaling pathways. One central pathway, which enables the cell to respond to various signals, is the Hippo pathway (Box 1) [10][11][12][13]. By highly context specific responses the Hippo pathway regulates cellular homeostasis and plays central roles in carcinogenesis and regenerative processes [10,12,13]. The Hippo pathway is extracellularly regulated by mechanical stimuli and diffusible chemicals. These signals are sensed in great part by receptors, such as G-protein coupled receptors (GPCRs) and adherence complexes embedded in the plasma membrane [1,[10][11][12][13][14][15][16]. To ensure a highly specific response, junctional complexes and receptors accumulate in distinct membrane structures and their plasma membrane abundance is furthermore dynamically regulated by exo-and endocytosis [3,4,7,17]. Junctional complexes provide robust cellular sensitivity of Hippo signaling to cell polarity and cell-cell contacts [10,15,16]. Catenins [18,19], protein tyrosine phosphatase nonreceptor (PTPN)14 [20,21], and the angiomotin family [22][23][24][25][26] play central roles in this regulation as direct YAP-binding proteins. Both PTPN14 and AMOT interact via PPxY motifs with WW domains of YAP and TAZ, and consequently, this interaction does not directly require YAP and TAZ Hippopathway-mediated phosphorylation [20][21][22][23]. Several of the Hippo ...

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A CTGF-YAP regulatory pathway is essential for angiogenesis and barriergenesis in the retina

Moon

Lee

Caesar

et al. 2020

Preprint

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Connective tissue growth factor (CTGF) or CCN2 is a matricellular protein essential for normal embryonic development and tissue repair. CTGF exhibits cell-and context-dependent activities, but the CTGF function in vascular development and permeability barrier is not known. Here we show that endothelial cells (ECs) are one of the major cellular sources of CTGF in the developing and adult retinal vasculature. Mice lacking CTGF expression either globally or specifically in ECs exhibit impaired vascular cell growth and morphogenesis, and blood barrier breakdown. The global molecular signature of CTGF includes cytoskeletal and extracellular matrix protein, growth factor, and transcriptional coregulator genes such as yes-associated protein (YAP). YAP, itself a transcriptional activator of the CTGF gene, mediates several CTGF-controlled angiogenic and barriergenic transcriptional programs. Re-expression of YAP rescues, at least partially, angiogenesis and barriergenesis in CTGF mutant mouse retinas. Thus, the CTGF-YAP angiomodulatory pathway is critical for vascular development and barrier function.

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Author response: YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development

Cited by 4 publications

References 0 publications

Endothelial Agrin Is Dispensable for Normal and Tumor Angiogenesis

Endothelial Agrin Is Dispensable for Normal and Tumor Angiogenesis

The Hippo Pathway, YAP/TAZ, and the Plasma Membrane

A CTGF-YAP regulatory pathway is essential for angiogenesis and barriergenesis in the retina

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