SALM4 regulates angiogenic functions in endothelial cells through VEGFR2 phosphorylation at Tyr1175

ABSTRACTAngiogenesis depends on VEGF‐mediated signaling. However, the regulatory mechanisms and functions of individual VEGF receptor 2 (VEGFR2) phosphorylation sites remain unclear. Here, we report that synaptic adhesion‐like molecule 4 (SALM4) regulates a specific VEGFR2 phosphorylation site. SALM4 silencing in HUVECs and Salm4 knockout (KO) in lung endothelial cells (ECs) of Salm4−/− mice suppressed phosphorylation of VEGFR2 tyrosine (Y) 1175 (Y1173 in mice) and downstream signaling upon VEGF‐A stimulation. However, VEGFR2 phosphorylation at Y951 (Y949 in mice) and Y1214 (Y1212 in mice) remained unchanged. Knockdown and KO of SALM4 inhibited VEGF‐A‐induced angiogenic functions of ECs. SALM4 depletion reduced endothelial leakage, sprouting, and migratory activities. Furthermore, in an ischemia and reperfusion (I/R) model, brain injury was attenuated in Salm4−/− mice compared with wild‐type (WT) mice. In brain lysates after I/R, VEGFR2 phosphorylation at Y949, Y1173, and Y1212 were induced in WT brains, but only Y1173 phosphorylation of VEGFR2 was reduced in Salm4−/− brains. Taken together, our results demonstrate that SALM4 specifically regulates VEGFR2 phosphorylation at Y1175 (Y1173 in mice), thereby fine‐tuning VEGF signaling in ECs.—Kim, D. Y., Park, J. A., Kim, Y., Noh, M., Park, S., Lie, E., Kim, E., Kim, Y.‐M., Kwon, Y.‐G. SALM4 regulates angiogenic functions in endothelial cells through VEGFR2 phosphorylation at Tyrll75. FASEB J. 33, 9842–9857 (2019). www.fasebj.org