ZFIN ID: ZDB-PUB-190821-7
CCN1 interlinks integrin and Hippo pathway to autoregulate tip cell activity
Park, M.H., Kim, A.K., Manandhar, S., Oh, S.Y., Jang, G.H., Kang, L., Lee, D.W., Hyeon, D.Y., Lee, S.H., Lee, H.E., Huh, T.L., Suh, S.H., Hwang, D., Byun, K., Park, H.C., Lee, Y.M.
Date: 2019
Source: eLIFE   8: (Journal)
Registered Authors: Huh, Tae-Lin, Park, Hae-Chul
Keywords: cell biology, developmental biology, mouse, zebrafish
MeSH Terms:
  • Animals
  • Cysteine-Rich Protein 61/genetics
  • Cysteine-Rich Protein 61/metabolism*
  • Endothelial Cells/physiology*
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Integrin alphaVbeta3/metabolism*
  • Mice, Transgenic
  • Neovascularization, Pathologic*
  • Protein Interaction Maps
  • Signal Transduction*
  • Vascular Endothelial Growth Factor Receptor-2/metabolism*
  • Zebrafish
PubMed: 31429823 Full text @ Elife
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.