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

Zebrafish
Gene Expression Regulation
Mice, Transgenic
Protein Interaction Maps
Signal Transduction*
Neovascularization, Pathologic*
Integrin alphaVbeta3/metabolism*
Endothelial Cells/physiology*
Animals
Cysteine-Rich Protein 61/genetics
Cysteine-Rich Protein 61/metabolism*
Humans
Vascular Endothelial Growth Factor Receptor-2/metabolism*
Human Umbilical Vein Endothelial Cells

(all 14)

PubMed

31429823 Full text @ Elife

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

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO1-ccn1l2	standard conditions	Prim-5	whole organism anterior-posterior axis fli1 expression increased amount, abnormal	Figure 1
AB + MO1-ccn1l2	standard conditions	Prim-5	whole organism anterior-posterior axis fli1 expression mislocalised, abnormal	Figure 1
AB + MO1-ccn1l2	standard conditions	Prim-15	dorsal aorta flt4 expression mislocalised, abnormal	Figure 1 figure supplement 1
AB + MO1-ccn1l2	standard conditions	Prim-15	dorsal aorta notch1b expression decreased amount, abnormal	Figure 1 figure supplement 1
AB + MO1-ccn1l2	standard conditions	Prim-15	intersegmental vessel notch1b expression decreased amount, abnormal	Figure 1 figure supplement 1
AB + MO1-ccn1l2	standard conditions	Prim-15	trunk fli1 expression spatial pattern, abnormal	Figure 1
AB + MO2-ccn1l2	standard conditions	Prim-5	whole organism anterior-posterior axis fli1 expression increased amount, abnormal	Figure 1
AB + MO2-ccn1l2	standard conditions	Prim-5	whole organism anterior-posterior axis fli1 expression mislocalised, abnormal	Figure 1
AB + MO2-ccn1l2	standard conditions	Prim-15	dorsal aorta flt4 expression mislocalised, abnormal	Figure 1 figure supplement 1
AB + MO2-ccn1l2	standard conditions	Prim-15	dorsal aorta notch1b expression decreased amount, abnormal	Figure 1 figure supplement 1

1 - 10 of 38

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
s843Tg	Tg(kdrl:EGFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
ccn1l2	MO1-ccn1l2	MRPHLNO
ccn1l2	MO2-ccn1l2	MRPHLNO

Fish

Fish
AB
AB + MO1-ccn1l2
AB + MO2-ccn1l2
s843Tg
s843Tg + MO1-ccn1l2
s843Tg + MO2-ccn1l2

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Park et al., 2019 ZDB-PUB-190821-7 PMID:31429823

CCN1 interlinks integrin and Hippo pathway to autoregulate tip cell activity

Park et al., 2019

ZDB-PUB-190821-7
PMID:31429823