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

Frederic Larrieu-Lahargue¹, Alana L Welm, Kirk R Thomas

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

Circulation Research

|July 30, 2011

Summary

This summary is machine-generated.

The alpha6beta1 (α6β1) integrin acts as a netrin-4 receptor in lymphatic endothelial cells. This finding identifies a potential therapeutic target for inhibiting netrin-4-driven cancer metastasis.

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Area of Science:

Vascular Biology
Cell Signaling
Integrin Biology

Background:

Netrin-4 plays a role in vascular development, but its endothelial receptor and functions remain unclear.
Netrin-4 signaling is not mediated by Unc5B and neogenin in lymphatic endothelial cells.
Integrins are known receptors for other netrin family members in non-endothelial cells.

Purpose of the Study:

To investigate if integrins function as netrin-4 receptors in endothelial cells.

Main Methods:

Assessed alpha6beta1 (α6β1) integrin expression in endothelial cells.
Examined netrin-4 binding to endothelial cells.
Inhibited alpha6 (α6) or beta1 (β1) integrin subunits to observe effects on netrin-4-induced cell functions.
Analyzed netrin-4-stimulated Src kinase family phosphorylation.
Colocalization studies of netrin-4 and alpha6beta1 (α6β1) integrin in mouse tissues.

Main Results:

Endothelial cells express alpha6beta1 (α6β1) integrin, which binds netrin-4.
Inhibition of alpha6 (α6) or beta1 (β1) subunits blocked netrin-4-induced endothelial cell migration, adhesion, and focal adhesion.
Netrin-4-stimulated Src kinase phosphorylation was abolished by alpha6 (α6) or beta1 (β1) inhibition.
Netrin-4 and alpha6beta1 (α6β1) integrin expression were found to colocalize in embryonic, intestinal, and tumor vasculature.

Conclusions:

The alpha6beta1 (α6β1) integrin serves as the netrin-4 receptor in lymphatic endothelium.
Alpha6beta1 (α6β1) integrin represents a potential therapeutic target to inhibit netrin-4-mediated metastatic dissemination.