ECSCR enhances KDR activation and promotes proteolysis of internalized KDR (LB160)

The endothelial cell‐specific chemotaxis receptor (ECSCR) is a cell‐surface protein selectively expressed by endothelial cells (ECs), with roles in EC migration, apoptosis and proliferation. Our previous study showed that loss of ECSCR in primary ECs reduced tyrosine phosphorylation of vascular endothelial growth factor (VEGF) receptor 2/kinase insert domain receptor (KDR) but not VEGF receptor 1/FLT1. Here, we show that ECSCR biochemically associates with KDR but not FLT1 and that the predicted ECSCR cytoplasmic and transmembrane regions can each confer association with KDR. Stimulation with VEGF165 rapidly and transiently increases ECSCR‐KDR complex formation, a process blocked by the KDR tyrosine kinase inhibitor compound SU5416 or inhibitors of endosomal acidification. Triple labeling experiments show VEGF‐stimulated KDR+/ECSCR+ intracellular co‐localization in a perinuclear intracellular locale. Silencing of ECSCR disrupts VEGF‐induced KDR activation and AKT and ERK phosphorylation and impairs VEGF‐stimulated KDR degradation. In zebrafish, ecscr interacts with kdrl during intersomitic vessel sprouting. Grant Funding Source : Supported by Children's Research Institute startup funds and American Heart Association Scientist Development Grant 11SDG5310020 (to G. A. W.).