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CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity.
Elife 2019; 8E

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.

Authors+Show Affiliations

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.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.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.BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.Department of Biomedical Sciences, Korea University, Ansan Hospital, Ansan, Republic of Korea.School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, 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.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 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.Department of Biomedical Sciences, Korea University, Ansan Hospital, Ansan, 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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31429823

Citation

Park, Myo-Hyeon, et al. "CCN1 Interlinks Integrin and Hippo Pathway to Autoregulate Tip Cell Activity." ELife, vol. 8, 2019.
Park MH, Kim AK, Manandhar S, et al. CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity. Elife. 2019;8.
Park, M. H., Kim, A. K., Manandhar, S., Oh, S. Y., Jang, G. H., Kang, L., ... Lee, Y. M. (2019). CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity. ELife, 8, doi:10.7554/eLife.46012.
Park MH, et al. CCN1 Interlinks Integrin and Hippo Pathway to Autoregulate Tip Cell Activity. Elife. 2019 Aug 20;8 PubMed PMID: 31429823.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity. AU - Park,Myo-Hyeon, AU - Kim,Ae Kyung, AU - Manandhar,Sarala, AU - Oh,Su-Young, AU - Jang,Gun-Hyuk, AU - Kang,Li, AU - Lee,Dong-Won, AU - Hyeon,Do Young, AU - Lee,Sun-Hee, AU - Lee,Hye Eun, AU - Huh,Tae-Lin, AU - Suh,Sang Heon, AU - Hwang,Daehee, AU - Byun,Kyunghee, AU - Park,Hae-Chul, AU - Lee,You Mie, Y1 - 2019/08/20/ PY - 2019/02/12/received PY - 2019/08/15/accepted PY - 2019/8/21/pubmed PY - 2019/8/21/medline PY - 2019/8/21/entrez KW - Cyr61 KW - VEGFR2 KW - YAP/TAZ KW - cell biology KW - developmental biology KW - integrinαvβ3 KW - mouse KW - zebrafish JF - eLife JO - Elife VL - 8 N2 - 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. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/31429823/CCN1_interlinks_integrin_and_Hippo_pathway_to_autoregulate_tip_cell_activity L2 - https://doi.org/10.7554/eLife.46012 DB - PRIME DP - Unbound Medicine ER -