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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Presenilins
Vascular Endothelial Growth Factor Receptor-1
Amyloid Precursor Protein Secretases
Phosphorylation
Vascular Endothelial Growth Factor Receptor
Presenilin-1
Class 3 Receptor-Like Protein Tyrosine Phosphatases
Endothelial cells
Vascular Endothelial Growth Factor A
Endothelial Cells
Valine
Up-Regulation
Mutagenesis
Protein Tyrosine Phosphatases
Alanine
Small Interfering RNA
Transfection

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

γ-secretase and presenilin mediate cleavage and phosphorylation of vascular endothelial growth factor receptor-1. / Cai, Jun; Chen, Zhijuan; Ruan, Qing; Han, Song; Liu, Li; Qi, Xiaoping; Boye, Sanford L.; Hauswirth, William W.; Grant, Maria B.; Boulton, Michael E.

In: Journal of Biological Chemistry, Vol. 286, No. 49, 09.12.2011, p. 42514-42523.

Research output: Contribution to journalArticle

Cai, J, Chen, Z, Ruan, Q, Han, S, Liu, L, Qi, X, Boye, SL, Hauswirth, WW, Grant, MB & Boulton, ME 2011, 'γ-secretase and presenilin mediate cleavage and phosphorylation of vascular endothelial growth factor receptor-1', Journal of Biological Chemistry, vol. 286, no. 49, pp. 42514-42523. https://doi.org/10.1074/jbc.M111.296590
Cai, Jun ; Chen, Zhijuan ; Ruan, Qing ; Han, Song ; Liu, Li ; Qi, Xiaoping ; Boye, Sanford L. ; Hauswirth, William W. ; Grant, Maria B. ; Boulton, Michael E. / γ-secretase and presenilin mediate cleavage and phosphorylation of vascular endothelial growth factor receptor-1. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 49. pp. 42514-42523.
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AU - Qi, Xiaoping

AU - Boye, Sanford L.

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AU - Grant, Maria B.

AU - Boulton, Michael E.

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