Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B.
Robo4 is an endothelial cell-specific member of the Roundabout axon guidance receptor family. To identify Robo4 binding partners, we performed a protein-protein interaction screen with the Robo4 extracellular domain. We find that Robo4 specifically binds to UNC5B, a vascular Netrin receptor, revealing unexpected interactions between two endothelial guidance receptors. We show that Robo4 maintains vessel integrity by activating UNC5B, which inhibits signaling downstream of vascular endothelial growth factor (VEGF). Function-blocking monoclonal antibodies against Robo4 and UNC5B increase angiogenesis and disrupt vessel integrity. Soluble Robo4 protein inhibits VEGF-induced vessel permeability and rescues barrier defects in Robo4(-/-) mice, but not in mice treated with anti-UNC5B. Thus, Robo4-UNC5B signaling maintains vascular integrity by counteracting VEGF signaling in endothelial cells, identifying a novel function of guidance receptor interactions in the vasculature.
Genentech Inc., South San Francisco, CA 94030, USA. alexander.koch@novartis.com
Alexander W
AW
Koch
Thomas
T
Mathivet
Bruno
B
Larrivée
Raymond K
RK
Tong
Joe
J
Kowalski
Laurence
L
Pibouin-Fragner
Karine
K
Bouvrée
Scott
S
Stawicki
Katrina
K
Nicholes
Nisha
N
Rathore
Suzie J
SJ
Scales
Elizabeth
E
Luis
Raquel
R
del Toro
Catarina
C
Freitas
Christiane
C
Bréant
Annie
A
Michaud
Pierre
P
Corvol
Jean-Léon
JL
Thomas
Yan
Y
Wu
Franklin
F
Peale
Ryan J
RJ
Watts
Marc
M
Tessier-Lavigne
Anil
A
Bagri
Anne
A
Eichmann
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002199:Capillary Permeability / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000075386:Netrin Receptors; D011485:Protein Binding / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D034421:Sus scrofa; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D019138:Antibodies, Blocking; D008024:Ligands; D009419:Nerve Tissue Proteins; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C540792:Robo4 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases