Myc‐dependent endothelial proliferation is controlled by phosphotyrosine 1212 in VEGF receptor‐2

Abstract

Exaggerated signaling by vascular endothelial growth factor (VEGF)‐A and its receptor, VEGFR2, in pathologies results in poor vessel function. Still, pharmacological suppression of VEGFA/VEGFR2 may aggravate disease. Delineating VEGFR2 signaling in vivo provides strategies for suppression of specific VEGFR2‐induced pathways. Three VEGFR2 tyrosine residues (Y949, Y1212, and Y1173) induce downstream signaling. Here, we show that knock‐in of phenylalanine to create VEGFR2 Y1212F in C57Bl/6 and FVB mouse strains leads to loss of growth factor receptor‐bound protein 2‐ and phosphoinositide 3′‐kinase (PI3K)p85 signaling. C57Bl/6 Vegfr2 Y1212F/Y1212F show reduced embryonic endothelial cell (EC) proliferation and partial lethality. FVB Vegfr2 Y1212F/Y1212F show reduced postnatal EC proliferation. Reduced EC proliferation in Vegfr2 Y1212F/Y1212F explants is rescued by c‐Myc overexpression. We conclude that VEGFR2 Y1212 signaling induces activation of extracellular‐signal‐regulated kinase (ERK)1/2 and Akt pathways required for c‐Myc‐dependent gene regulation, endothelial proliferation, and vessel stability.