CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31429823.
- Also identified by DOI 10.7554/eLife.46012 and PMC identifier 6726423.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <i>ccn1</i>-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 <i>Ccn1</i> transgenic mice, and allograft tumours in <i>Ccn1</i> transgenic mice showed hyperactive vascular sprouting. Cancer patients with high <i>CCN1</i> expression have poor survival outcomes and positive correlation with <i>ITGAV and ITGB3</i> and high <i>YAP/WWTR1</i>. 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.
Medical subject headings
- Cysteine-Rich Protein 61
- Endothelial Cells
- Integrin alphaVbeta3
- Neovascularization, Pathologic
- Signal Transduction
- Vascular Endothelial Growth Factor Receptor-2