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Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B
Authors:Koch Alexander W  Mathivet Thomas  Larrivée Bruno  Tong Raymond K  Kowalski Joe  Pibouin-Fragner Laurence  Bouvrée Karine  Stawicki Scott  Nicholes Katrina  Rathore Nisha  Scales Suzie J  Luis Elizabeth  del Toro Raquel  Freitas Catarina  Bréant Christiane  Michaud Annie  Corvol Pierre  Thomas Jean-Léon  Wu Yan  Peale Franklin  Watts Ryan J  Tessier-Lavigne Marc  Bagri Anil  Eichmann Anne
Institution:Genentech Inc., South San Francisco, CA 94030, USA. alexander.koch@novartis.com
Abstract: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.
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