TY - JOUR TI - 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 A2 - Cooper, Jonathan A A2 - Koh, Gou Young A2 - Chen, Hong VL - 8 PY - 2019 DA - 2019/08/20 SP - e46012 C1 - eLife 2019;8:e46012 DO - 10.7554/eLife.46012 UR - https://doi.org/10.7554/eLife.46012 AB - 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. KW - Cyr61 KW - integrinαvβ3 KW - VEGFR2 KW - YAP/TAZ JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -