Pleiotrophin selectively binds to vascular endothelial growth factor receptor 2 and inhibits or stimulates cell migration depending on ανβ3 integrin expression.

Angiogenesis
Margarita LamprouEvangelia Papadimitriou

Abstract

Pleiotrophin (PTN) has a moderate stimulatory effect on endothelial cell migration through ανβ3 integrin, while it decreases the stimulatory effect of vascular endothelial growth factor A (VEGFA) and inhibits cell migration in the absence of ανβ3 through unknown mechanism(s). In the present work, by using a multitude of experimental approaches, we show that PTN binds to VEGF receptor type 2 (VEGFR2) with a KD of 11.6 nM. Molecular dynamics approach suggests that PTN binds to the same VEGFR2 region with VEGFA through its N-terminal domain. PTN inhibits phosphorylation of VEGFR2 at Tyr1175 and still stimulates endothelial cell migration in the presence of a selective VEGFR2 tyrosine kinase inhibitor. VEGFR2 downregulation by siRNA or an anti-VEGFR2 antibody that binds to the ligand-binding VEGFR2 domain also induce endothelial cell migration, which is abolished by a function-blocking antibody against ανβ3 or the peptide PTN112-136 that binds ανβ3 and inhibits PTN binding. In cells that do not express ανβ3, PTN decreases both VEGFR2 Tyr1175 phosphorylation and cell migration in a VEGFR2-dependent manner. Collectively, our data identify VEGFR2 as a novel PTN receptor involved in the regulation of cell migration by PTN and contribut...Continue Reading

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Methods Mentioned

BETA
transfection
proximity ligation assay
Chip
glycosylation
biosensor

Software Mentioned

siNeg
UCSF Chimera
BIAevaluation
ImageJ
AMBER14
ff14SB

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