γ-secretase and presenilin mediate cleavage and phosphorylation of vascular endothelial growth factor receptor-1

Jun Cai, Zhijuan Chen, Qing Ruan, Song Han, Li Liu, Xiaoping Qi, Sanford L. Boye, William W. Hauswirth, Maria B. Grant, Michael E. Boulton

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30 Scopus citations

Abstract

We have reported previously that pigment epithelium-derived factor (PEDF) can, via γ-secretase-mediated events, inhibit VEGF-induced angiogenesis in microvascular endothelial cells by both (a) cleavage and intracellular translocation of a C-terminal fragment of VEGF receptor-1 (VEGFR1) and (b) inhibition of VEGF-induced phosphorylation of VEGFR1. Using site-direct mutagenesis and transfection of wild type and mutated receptors into endothelial cells, we showed that transmembrane cleavage of VEGFR1 occurs at valine 767 and that a switch from valine to alanine at this position prevented cleavage and formation of a VEGFR1 intracellular fragment. Using siRNA to selectively knock down protein-tyrosine phosphatases (PTPs) in endothelial cells, we demonstrated that vascular endothelial PTP is responsible for dephosphorylation of activated VEGFR1. PEDF up-regulation of full-length presenilin 1 (Fl.PS1) facilitated the association of vascular endothelial PTP and VEGFR1. Knockdown of Fl.PS1 prevented dephosphorylation of VEGFR1, whereas up-regulation of Fl.PS1 stimulated VEGFR1 dephosphorylation. Fl.PS1 associated with VEGFR1 within 15 min after PEDF treatment. In conclusion, we determined the PEDF-mediated events responsible for VEGFR1 signaling and identified full-length presenilin as a critical adaptor molecule in the dephosphorylation of VEGFR1. This greater understanding of the regulation of VEGFR1 signaling will help identify novel anti-VEGF therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)42514-42523
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number49
DOIs
StatePublished - Dec 9 2011

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cai, J., Chen, Z., Ruan, Q., Han, S., Liu, L., Qi, X., Boye, S. L., Hauswirth, W. W., Grant, M. B., & Boulton, M. E. (2011). γ-secretase and presenilin mediate cleavage and phosphorylation of vascular endothelial growth factor receptor-1. Journal of Biological Chemistry, 286(49), 42514-42523. https://doi.org/10.1074/jbc.M111.296590