CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity

Park Myo-Hyeon, Ae Kyung Kim, Sarala Manandhar, Oh Su-Young, Jang Gun-Hyuk, Li Kang, Lee Dong-Won, Do Young Hyeon, Lee Sun-Hee, Hye Eun Lee, Huh Tae-Lin, Sang Heon Suh, Daehee Hwang, Kyunghee Byun, Park Hae-Chul, You Mie Lee

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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 ccn7-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 avP3 through CCN1. Integrin avP3 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 avP3/VEGFR2 and increased YAP/TAZ activity, suggesting a promising therapeutic intervention for pathological angiogenesis.

Original languageEnglish
Article numbere46012
JournaleLife
Volume8
DOIs
Publication statusPublished - 2019 Aug

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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