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A repressor sequence in the juxtamembrane domain of Flt‐1 (VEGFR‐1) constitutively inhibits vascular endothelial growth factor‐dependent phosphatidylinositol 3′‐kinase activation and endothelial cell migration
Author(s) -
Gille Hendrik,
Kowalski Joe,
Yu Lanlan,
Chen Helen,
Pisabarro M.Teresa,
DavisSmyth Terri,
Ferrara Napoleone
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.15.4064
Subject(s) - library science , phosphatidylinositol , medicine , history , kinase , biology , computer science , genetics
Vascular endothelial growth factor (VEGF) has two highly homologous tyrosine kinase receptors: Flt‐1 (VEGFR‐1) and KDR (VEGFR‐2). KDR is strongly phosphorylated on tyrosines and can transmit mitogenic and motogenic signals following VEGF binding, while Flt‐1 is markedly less effective in mediating such functions. To dissect the regions that account for the differences between the two receptors, we generated a series of chimeric Flt‐1–KDR molecules. We found that the juxtamembrane region of Flt‐1 prevents key signaling functions. When the juxtamembrane region of Flt‐1 is replaced by that of KDR, Flt‐1 becomes competent to mediate endothelial cell migration and phosphatidylinositol 3′‐kinase activation in response to VEGF. Further mutational analysis shows that a short divergent sequence is responsible for such repressor function. However, mutant Flt‐1 receptors lacking this sequence do not transmit effective proliferative signals, suggesting that this receptor function is regulated separately. These results define a novel functional domain that serves to repress Flt‐1 activity in endothelial cells.