CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity

eLife

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[1] BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea;BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea;School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea;Department of Biomedical Sciences, Korea University, Ansan Hospital, Ansan, Republic of Korea;Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Korea;Department of New Biology and Center for Plant Aging Research, DGIST, Daegu, Republic of Korea;Gachon University, School of Medicine, Incheon, Republic of Korea;School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea;School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea;

关键词: Cyr61;    integrinαvβ3;    VEGFR2;    YAP/TAZ;    Mouse;    Zebrafish;   

DOI  :  10.7554/eLife.46012

来源: publisher

【 摘 要 】

10.7554/eLife.46012.001CCN1 (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.

【 授权许可】

CC BY