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Ligand induced activation of VEGFR during angiogenesis
Author(s) -
Li Xiaobo,
Xu Ping,
Toombs Jason E.,
Parker Matthew W.,
Brekken Rolf A.,
Vander Kooi Craig W.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.971.2
Subject(s) - angiogenesis , regulator , ligand (biochemistry) , chemistry , tyrosine kinase , microbiology and biotechnology , receptor tyrosine kinase , vascular endothelial growth factor , kinase insert domain receptor , signal transduction , receptor , vegf receptors , negative regulator , cancer research , biology , vascular endothelial growth factor a , biochemistry , gene
Vascular endothelial growth factor (VEGF) is one of the most potent pro‐angiogenic growth factors and a key regulator of both physiological and pathological angiogenesis. VEGF signals through VEGF receptor (VEGFR) tyrosine kinase family members. VEGFR‐2 is a main regulator of angiogenic effects of VEGF under both normal and abnormal conditions. VEGF binding to VEGFR‐2 induces specific dimerization and subsequent activation of angiogenesis. A model of VEGFR‐2 activation shows that ligand binding induces specific dimerization of the juxtamembrane D7 domain of VEGFR‐2. We report here the high‐resolution structure of the VEGFR‐2 Ig d7 dimer with a molecular interface centered around R724 that is primarily composed of salt‐bridges and hydrogen bonds. We further demonstrate a monoclonal antibody that binds to the D7 dimerization interface in a manner that is mutually exclusive with dimerization. We further show that antibody binding reduces VEGFR‐2 signaling. Taken together, these results indicate that ligand binding is necessary but not sufficient for VEGFR‐2 activation and define a new potential mechanism for therapeutic intervention. Supported by NIH Grant GM094155.