Pleiotrophin selectively binds to vascular endothelial growth factor receptor 2 and inhibits or stimulates cell migratio
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ORIGINAL PAPER
Pleiotrophin selectively binds to vascular endothelial growth factor receptor 2 and inhibits or stimulates cell migration depending on ανβ3 integrin expression Margarita Lamprou1 · Pinelopi Kastana1 · Fani Kofina1 · Ηaralampos Tzoupis2 · Spyridoula Barmpoutsi1 · Md Sanaullah Sajib3 · Marina Koutsioumpa1,5 · Evangelia Poimenidi1,6 · Aikaterini A. Zompra4 · Dimitrios Tassopoulos1 · Effrosyni Choleva1 · Theodore Tselios2 · Constantinos M. Mikelis3 · Evangelia Papadimitriou1 Received: 19 December 2019 / Accepted: 6 July 2020 © Springer Nature B.V. 2020
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 contribute to the elucidation of the mechanism of activation of endothelial cell migration through the interplay between VEGFR2 and ανβ3. Keywords Angiogenesis · Endothelial cells · Growth factors · Integrins · Migration · Vascular endothelial growth factor
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09733-x) contains supplementary material, which is available to authorized users. * Evangelia Papadimitriou [email protected] 1
Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, 26504 Patras, Greece
2
Department of Chemistry, University of Patras, Patras, Greece
3
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
4
Laboratory of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, University of Patras, 26504 Patras, Greece
Pleiotrophin (PTN) is a secreted growth factor known to have a regulatory role in physiological and pathological angiogenesis. PTN consists of two β-sheet structures 5
Present Address: Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen
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