Targeting the interaction of pleiotrophin and VEGFA165 with protein tyrosine phosphatase receptor zeta 1 inhibits endothelial cell activation and angiogenesis

Eur J Pharmacol. 2024 Aug 15:977:176692. doi: 10.1016/j.ejphar.2024.176692. Epub 2024 May 29.

Abstract

Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a transmembrane tyrosine phosphatase (TP) that serves as a receptor for pleiotrophin (PTN) and vascular endothelial growth factor A 165 (VEGFA165) to regulate endothelial cell migration. In the present work, we identify a PTN peptide fragment (PTN97-110) that inhibits the interaction of PTN and VEGFA165 with PTPRZ1 but not VEGF receptor 2. This peptide abolishes the stimulatory effect of PTN and VEGFA165 on endothelial cell migration, tube formation on Matrigel, and Akt activation in vitro. It also partially inhibits VEGFA165-induced VEGF receptor 2 activation but does not affect ERK1/2 activation and cell proliferation. In vivo, PTN97-110 inhibits or dysregulates angiogenesis in the chick embryo chorioallantoic membrane and the zebrafish assays, respectively. In glioblastoma cells in vitro, PTN97-110 abolishes the stimulatory effect of VEGFA165 on cell migration and inhibits their anchorage-independent growth, suggesting that this peptide might also be exploited in glioblastoma therapy. Finally, in silico and experimental evidence indicates that PTN and VEGFA165 bind to the extracellular fibronectin type-III (FNIII) domain to stimulate cell migration. Collectively, our data highlight novel aspects of the interaction of PTN and VEGFA165 with PTPRZ1, strengthen the notion that PTPRZ1 is required for VEGFA165-induced signaling, and identify a peptide that targets this interaction and can be exploited for the design of novel anti-angiogenic and anti-glioblastoma therapeutic approaches.

Keywords: Angiogenesis inhibition; Endothelial; Glioblastoma; PTPRZ1; Tyrosine phosphatase; VEGFA.

MeSH terms

  • Angiogenesis
  • Animals
  • Carrier Proteins* / metabolism
  • Carrier Proteins* / pharmacology
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Cell Proliferation / drug effects
  • Chick Embryo
  • Cytokines* / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Human Umbilical Vein Endothelial Cells* / drug effects
  • Humans
  • Neovascularization, Pathologic
  • Neovascularization, Physiologic* / drug effects
  • Protein Binding
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5* / metabolism
  • Vascular Endothelial Growth Factor A* / metabolism
  • Vascular Endothelial Growth Factor A* / pharmacology
  • Zebrafish

Substances

  • pleiotrophin
  • Vascular Endothelial Growth Factor A
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5
  • Cytokines
  • Carrier Proteins
  • VEGFA protein, human
  • PTPRZ1 protein, human