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Cleaved Flt1 ectodomain antagonizes VEGF‐A signaling while uncleaved Flt1 facilitates KDR signaling
Author(s) -
Raikwar Nandita,
Liu Kang,
Thomas Christie
Publication year - 2015
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.29.1_supplement.796.4
Subject(s) - ectodomain , angiogenesis , microbiology and biotechnology , kinase insert domain receptor , chemistry , receptor tyrosine kinase , extracellular , receptor , signal transduction , tyrosine kinase , vascular endothelial growth factor , biology , cancer research , vascular endothelial growth factor a , biochemistry , vegf receptors
Flt1 and KDR are membrane‐bound tyrosine kinase receptors that can bind VEGF‐A as homo or heterodimers and regulate angiogenesis and vasculogenesis. Flt1 has a 10‐fold higher affinity for VEGF‐A and brings VEGF‐A in proximity to KDR to regulate the effects of VEGF‐A on KDR signaling. We have shown that Flt1 is proteolytically cleaved to release an ectodomain into the extracellular milieu which can inhibit VEGF‐A induced angiogenesis. We co‐expressed Flt1 and KDR in HEK293 cells and studied their interaction, Flt1 cleavage and KDR function. Increasing KDR expression reduces Flt1 ectodomain cleavage and enhances the abundance of uncleaved Flt1 in cell lysates. KDR overexpression stimulates sFlt1 secretion into the extracellular space and progressively reduces free VEGF‐A. Co‐expression of Flt1 in the presence of KDR increases downstream signaling over that seen with KDR alone. Flt1 ligands, VEGF‐A and PLGF reduces ectodomain cleavage of Flt1 where as VEGF‐E, a KDR‐specific ligand does not. These results suggest that uncleaved Flt1 bound to KDR competes with extracellular sFlt1 and increases receptor activation. Our data also suggests that ligand binding promotes receptor activation by reducing ectodomain receptor cleavage. NIDDK