CCN1 interlinks integrin and Hippo pathway to autoregulate tip cell activity
- Kyungpook National University, Republic of Korea
- Korea University, Ansan Hospital, Republic of Korea
- POSTECH, Republic of Korea
- Chonnam National University Hospital, Republic of Korea
- Daegu Gyeongbuk Institute of Science and Technology, Republic of Korea
- Gachon University, Republic of Korea
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.
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All data generated or analysed during this study are included in the manuscript and supporting files
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Funding
National Research Foundation of Korea (NRF-2013R1A2A2A01068868)
- You Mie Lee
National Research Foundation of Korea (NRF-2017R1A2B3002227)
- You Mie Lee
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The animal handling and experimental procedures were strictly conducted as per the Guidelines for Care and Use of Laboratory Animals issued by the Institutional Ethical Animal Care Committee of Kyungpook National University
Copyright
© 2019, Park et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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CCN1 interlinks integrin and Hippo pathway to autoregulate tip cell activity
eLife 8:e46012.
https://doi.org/10.7554/eLife.46012
