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CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity

Title
CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity
Authors
Park, Myo-HyeonKim, Ae kyungManandhar, SaralaOh, Su-YoungJang, Gun-HyukKang, LiLee, Dong-WonHyeon, Do YoungLee, Sun-HeeLee, Hye EunHuh, Tae-Lin.Suh, Sang Heon.Hwang, DaeheeByun, KyungheePark, Hae-ChulLee, You Mie
DGIST Authors
Hwang, Daehee
Issue Date
2019-08
Citation
eLife, 8
Type
Article
Article Type
Article
Author Keywords
mouseVEGFR2YAP/TAZzebrafishcell biologyCyr61developmental biologyintegrinαvβ3
Keywords
IMMEDIATE-EARLY GENEMATRICELLULAR PROTEIN CCN1ENDOTHELIAL-CELLSEXTRACELLULAR-MATRIXBREAST-CANCERUP-REGULATIONFACTOR CYR61GROWTHVEGFANGIOGENESIS
ISSN
2050-084X
Abstract
CCN1 (CYR61) stimulates active angiogenesis in various tumours, although the mechanism is largely unknown. Here, we report that CCN1 is a key regulator of endothelial tip cell activity in angiogenesis. Microvessel networks and directional vascular cell migration patterns were deformed in ccn1-knockdown zebrafish embryos. CCN1 activated VEGFR2 and downstream MAPK/PI3K signalling pathways, YAP/TAZ, as well as Rho effector mDia1 to enhance tip cell activity and CCN1 itself. VEGFR2 interacted with integrin αvβ3 through CCN1. Integrin αvβ3 inhibitor repressed tip cell number and sprouting in postnatal retinas from endothelial cell-specific Ccn1 transgenic mice, and allograft tumours in Ccn1 transgenic mice showed hyperactive vascular sprouting. Cancer patients with high CCN1 expression have poor survival outcomes and positive correlation with ITGAV and ITGB3 and high YAP/WWTR1. Thus, our data underscore the positive feedback regulation of tip cells by CCN1 through integrin αvβ3/VEGFR2 and increased YAP/TAZ activity, suggesting a promising therapeutic intervention for pathological angiogenesis. © 2019, Park et al.
URI
http://hdl.handle.net/20.500.11750/10961
DOI
10.7554/eLife.46012
Publisher
eLife Sciences Publications
Related Researcher
  • Author Hwang, Daehee Systems Biology and Medicine Lab
  • Research Interests Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
Files:
Collection:
Department of New BiologySystems Biology and Medicine Lab1. Journal Articles


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