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Circ Res. 2011 Sep 16;109(7):770-4. doi: 10.1161/CIRCRESAHA.111.247239. Epub 2011 Jul 28.

Netrin-4 activates endothelial integrin {alpha}6{beta}1.

Author information

1
University of Utah, Eccles Institute of Human Genetics, Salt Lake City, UT 84112, USA.

Abstract

RATIONALE:

Netrin-4 regulates vascular development. Identity of netrin-4 endothelial receptor and its subsequent cell functions is controversial. We previously demonstrated that the inhibition of netrin-1 canonical receptors, Unc5B and neogenin, expressed by lymphatic endothelial cells, do not suppress netrin-4-induced cell signaling and functions. Netrin family members were shown to signal through a range of receptors, including integrins (such as α3β1, α6β1, and α6β4) in nonendothelial cells.

OBJECTIVE:

We tested whether integrins are netrin-4 receptors in the endothelium.

METHODS AND RESULTS:

The α6β1 integrin is expressed by endothelial cells, and binds netrin-4 in a dose-dependent manner. Inhibition of α6 or β1 integrin subunits suppresses netrin-4-induced endothelial cell migration, adhesion, and focal adhesion contact. Netrin-4-stimulated phosphorylation of Src kinase family, effectors of endothelial cell migration, is also abolished by α6 or β1 inhibition. Finally, netrin-4 and α6β1 integrin expression colocalize in mouse embryonic, intestine, and tumor vasculature.

CONCLUSIONS:

The α6β1 integrin is a netrin-4 receptor in lymphatic endothelium and consequently represents a potential target to inhibit netrin-4-induced metastatic dissemination.

PMID:
21799154
PMCID:
PMC3552560
DOI:
10.1161/CIRCRESAHA.111.247239
[Indexed for MEDLINE]
Free PMC Article

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