γ-Secretase and Presenilin Mediate Cleavage and Phosphorylation of Vascular Endothelial Growth Factor Receptor-1

被引:37
作者
Cai, Jun [1 ]
Chen, Zhijuan [1 ]
Ruan, Qing [1 ]
Han, Song [2 ]
Liu, Li [3 ]
Qi, Xiaoping [1 ]
Boye, Sanford L. [4 ]
Hauswirth, William W. [4 ]
Grant, Maria B. [3 ]
Boulton, Michael E. [1 ]
机构
[1] Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA
[2] Univ Florida, Dept Surg, Gainesville, FL 32610 USA
[3] Univ Florida, Dept Pharmacol & Therapeut, Gainesville, FL 32610 USA
[4] Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA
基金
美国国家卫生研究院;
关键词
REGULATED INTRAMEMBRANE PROTEOLYSIS; PROTEIN-TYROSINE PHOSPHATASES; VE-PTP; ANGIOGENESIS; COMPLEX; CANCER; CELL; IDENTIFICATION; ASSOCIATION; EXPRESSION;
D O I
10.1074/jbc.M111.296590
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
We have reported previously that pigment epithelium-derived factor (PEDF) can, via gamma-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.
引用
收藏
页码:42514 / 42523
页数:10
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