Pigment epithelium-derived factor inhibits angiogenesis via regulated intracellular proteolysis of vascular endothelial growth factor receptor 1 (Withdrawn Publication. See vol. 298, 2021)
Pigment epithelium-derived factor inhibits angiogenesis via regulated intracellular proteolysis of vascular endothelial growth factor receptor 1 (Withdrawn Publication. See vol. 298, 2021)
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DOI：
10.1074/jbc.m507401200
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发表时间：
2006-02-10
影响因子：
4.8
通讯作者：
Boulton, M
中科院分区：
文献类型：
--
作者：
Cai, J;Jiang, WG;Boulton, M
色素上皮衍生因子（PEDF）是一种内源性血管生长负调节因子。在这里，我们报告，PEDF是能够抑制生长因子诱导的血管生成的微血管内皮细胞通过一种新的途径，需要切割和细胞内易位的跨膜结构域的VEGFR-1。VEGFR-1的亚细胞分布分析显示，在用VEGF和PEDF处理的细胞的胞质溶胶中出现了80 kDa的C-末端结构域，其与核和细胞骨架组分中全长受体的减少相关。这种受调节的膜内蛋白水解依赖于γ-分泌酶，因为γ-分泌酶的抑制消除了PEDF对VEGF诱导的血管生成以及VEGFR-1裂解的抑制作用。即使在没有VEGF的情况下，向微血管内皮细胞中加入PEDF也显著增加了γ-分泌酶活性，表明VEGF与VEGF-R1的结合对于底物的可用性是必不可少的。这种活性的增加与早老素1从核周区到细胞膜的易位有关。PEDF还能够抑制VEGF诱导的VEGFR-1磷酸化。总之，我们已经确定了两个新的途径，PEDF抑制VEGF诱导的血管生成：调节膜内蛋白水解和抑制磷酸化。这证实了PEDF和VEGFR-1在血管生成负调控中的重要性。
Pigment epithelium-derived factor ( PEDF) has been identified as one of the most potent of endogenous negative regulators of blood vessel growth in the body. Here we report that PEDF is able to inhibit growth factor-induced angiogenesis in microvascular endothelial cells through a novel pathway requiring cleavage and intracellular translocation of the transmembrane domain of the VEGFR-1. Analysis of the subcellular distribution of VEGFR-1 revealed the appearance of an 80-kDa C-terminal domain in the cytosol of cells treated with VEGF and PEDF that correlated with a decrease of the full-length receptor in the nuclear and cytoskeletal fractions. This regulated intramembrane proteolysis is dependent on gamma-secretase because inhibition of gamma-secretase abolished the inhibitory effect of PEDF on VEGF-induced angiogenesis as well as VEGFR-1 cleavage. The addition of PEDF to microvascular endothelial cells significantly increases gamma-secretase activity even in the absence of VEGF, showing that VEGF binding to VEGF-R1 is essential for substrate availability. This increase in activity was associated with translocation of presenilin 1 from the perinuclear region to the cell membrane. PEDF was also able to inhibit VEGF-induced phosphorylation of VEGFR-1. Taken together we have identified two novel pathways by which PEDF inhibits VEGF-induced angiogenesis: regulated intramembrane proteolysis and inhibition of phosphorylation. This confirms the importance of PEDF and VEGFR-1 in the negative regulation of angiogenesis.