CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity
Myo-Hyeon Park,
Ae kyung Kim,
Sarala Manandhar,
Su-Young Oh,
Gun-Hyuk Jang,
Li Kang,
Dong-Won Lee,
Do Young Hyeon,
Sun-Hee Lee,
Hye Eun Lee,
Tae-Lin Huh,
Sang Heon Suh,
Daehee Hwang,
Kyunghee Byun,
Hae-Chul Park,
You Mie Lee
Affiliations
Myo-Hyeon Park
BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
Ae kyung Kim
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
Sarala Manandhar
BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
Su-Young Oh
BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
Gun-Hyuk Jang
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
Li Kang
BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
Dong-Won Lee
Department of Biomedical Sciences, Korea University, Ansan Hospital, Ansan, Republic of Korea
Do Young Hyeon
School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea
Sun-Hee Lee
BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
Hye Eun Lee
BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
Tae-Lin Huh
School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
Sang Heon Suh
Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Korea
Daehee Hwang
Department of New Biology and Center for Plant Aging Research, DGIST, Daegu, Republic of Korea
Kyunghee Byun
Gachon University, School of Medicine, Incheon, Republic of Korea
Hae-Chul Park
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
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.
