[HTML][HTML] Proteolytic processing regulates receptor specificity and activity of VEGF‐C

V Joukov, T Sorsa, V Kumar, M Jeltsch… - The EMBO …, 1997 - embopress.org
V Joukov, T Sorsa, V Kumar, M Jeltsch, L Claesson‐Welsh, Y Cao, O Saksela, N Kalkkinen…
The EMBO journal, 1997embopress.org
The recently identified vascular endothelial growth factor C (VEGF‐C) belongs to the platelet‐
derived growth factor (PDGF)/VEGF family of growth factors and is a ligand for the
endothelial‐specific receptor tyrosine kinases VEGFR‐3 and VEGFR‐2. The VEGF
homology domain spans only about one‐third of the cysteine‐rich VEGF‐C precursor. Here
we have analysed the role of post‐translational processing in VEGF‐C secretion and
function, as well as the structure of the mature VEGF‐C. The stepwise proteolytic processing …
Abstract
The recently identified vascular endothelial growth factor C (VEGF‐C) belongs to the platelet‐derived growth factor (PDGF)/VEGF family of growth factors and is a ligand for the endothelial‐specific receptor tyrosine kinases VEGFR‐3 and VEGFR‐2. The VEGF homology domain spans only about one‐third of the cysteine‐rich VEGF‐C precursor. Here we have analysed the role of post‐translational processing in VEGF‐C secretion and function, as well as the structure of the mature VEGF‐C. The stepwise proteolytic processing of VEGF‐C generated several VEGF‐C forms with increased activity towards VEGFR‐3, but only the fully processed VEGF‐C could activate VEGFR‐2. Recombinant ‘mature’VEGF‐C made in yeast bound VEGFR‐3 (K D= 135 pM) and VEGFR‐2 (K D= 410 pM) and activated these receptors. Like VEGF, mature VEGF‐C increased vascular permeability, as well as the migration and proliferation of endothelial cells. Unlike other members of the PDGF/VEGF family, mature VEGF‐C formed mostly non‐covalent homodimers. These data implicate proteolytic processing as a regulator of VEGF‐C activity, and reveal novel structure–function relationships in the PDGF/VEGF family.
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