title: Netrin-4 activates endothelial integrin {alpha}6{beta}1.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: University of Utah, Eccles Institute of Human Genetics, Salt Lake City, UT 84112, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Larrieu-Lahargue
authors.forename: Alana L
authors.initials: AL
authors.lastname: Welm
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Thomas
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000196:embryology / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D039121:Integrin alpha6beta1 / Q000235:genetics / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply; D042601:Lymphatic Vessels / Q000378:metabolism; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075385:Netrins; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D039121:Integrin alpha6beta1; C498815:NTN4 protein, human; D009414:Nerve Growth Factors; D000075385:Netrins; C416214:Ntn4 protein, mouse; D011994:Recombinant Proteins; D019061:src-Family Kinases