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Protein kinase C, VEGF and ADAM metalloproteases regulate proteolytic cleavage of Flt1 to control the abundance of a functionally active ectodomain (679.3)
Author(s) -
Raikwar Nandita,
Liu Kang,
Thomas Christie
Publication year - 2014
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.28.1_supplement.679.3
Subject(s) - ectodomain , adam10 , microbiology and biotechnology , receptor tyrosine kinase , angiogenesis , metalloproteinase , tyrosine kinase , chemistry , vascular endothelial growth factor , kinase insert domain receptor , signal transduction , biology , vascular endothelial growth factor a , matrix metalloproteinase , receptor , cancer research , disintegrin , biochemistry , vegf receptors
Flt1 or VEGFR1 (vascular endothelial growth factor receptor‐1/fms‐related tyrosine kinase 1) is a tyrosine kinase receptor that regulates angiogenesis by sequestering VEGF from its signaling receptor Flk1 or VEGFR2. We have previously described the proteolytic release of an ectodomain of Flt1 that can also function as an angiogenesis inhibitor (Exp Cell Res 2013). We demonstrate that the metalloprotease inhibitor GM6001 reduces the abundance of sFlt1 in conditioned media in vascular endothelial cells consistent with the notion that sFlt1 arises in part via metalloprotease activity. Flt1 cleavage is increased by overexpression of ADAM10 and ADAM 17 while knockdown of either ADAM10 or ADAM17 reduced cleavage in HEK cells confirming that these metalloproteases regulate Flt1 ectodomain release. Interestingly, PMA stimulates Flt1 ectodomain cleavage while VEGF inhibits Flt1 ectodomain cleavage and neither requires the C‐terminal tyrosine kinase domains. Proteolytic cleavage of Flt1 can be regulated independently of ligand binding and intracellular signaling. NIDDK