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Myc‐dependent endothelial proliferation is controlled by phosphotyrosine 1212 in VEGF receptor‐2
Author(s) -
Testini Chiara,
Smith Ross O,
Jin Yi,
Martinsson Pernilla,
Sun Ying,
Hedlund Marie,
SáinzJaspeado Miguel,
Shibuya Masabumi,
Hellström Mats,
ClaessonWelsh Lena
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201947845
Subject(s) - receptor , microbiology and biotechnology , vegf receptors , chemistry , cancer research , biology , biochemistry
Exaggerated signaling by vascular endothelial growth factor ( VEGF )‐A and its receptor, VEGFR 2, in pathologies results in poor vessel function. Still, pharmacological suppression of VEGFA / VEGFR 2 may aggravate disease. Delineating VEGFR 2 signaling in vivo provides strategies for suppression of specific VEGFR 2‐induced pathways. Three VEGFR 2 tyrosine residues (Y949, Y1212, and Y1173) induce downstream signaling. Here, we show that knock‐in of phenylalanine to create VEGFR 2 Y1212F in C57Bl/6 and FVB mouse strains leads to loss of growth factor receptor‐bound protein 2‐ and phosphoinositide 3′‐kinase ( PI 3K)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 VEGFR 2 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.