PUBLICATION
CCN1 interlinks integrin and Hippo pathway to autoregulate tip cell activity
- Authors
- 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.
- ID
- ZDB-PUB-190821-7
- Date
- 2019
- Source
- eLIFE 8: (Journal)
- Registered Authors
- Huh, Tae-Lin, Park, Hae-Chul
- Keywords
- cell biology, developmental biology, mouse, zebrafish
- MeSH Terms
-
- Animals
- Vascular Endothelial Growth Factor Receptor-2/metabolism*
- Integrin alphaVbeta3/metabolism*
- Zebrafish
- Gene Expression Regulation
- Protein Interaction Maps
- Human Umbilical Vein Endothelial Cells
- Neovascularization, Pathologic*
- Endothelial Cells/physiology*
- Signal Transduction*
- Humans
- Mice, Transgenic
- Cysteine-Rich Protein 61/genetics
- Cysteine-Rich Protein 61/metabolism*
- PubMed
- 31429823 Full text @ Elife
Citation
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. (2019) CCN1 interlinks integrin and Hippo pathway to autoregulate tip cell activity. eLIFE. 8:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping