Identification of ligand-induced proteolytic cleavage and ectodomain shedding of VEGFR-1/FLT1 in leukemic cancer cells.
Identification of ligand-induced proteolytic cleavage and ectodomain shedding of VEGFR-1/FLT1 in leukemic cancer cells.
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DOI：
10.1158/0008-5472.can-08-2905
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Meyer RD
中科院分区：
文献类型：
--
作者：
Rahimi N;Golde TE;Meyer RD
血管内皮生长因子受体-1/FMS相关酪氨酸激酶1(VEGFR-1/Flt1)是一种膜结合受体酪氨酸激酶，也是一种选择性剪接的可溶性蛋白(sVEGFR-1)，含有其胞外区的1-6个免疫球蛋白样结构域。SVEGFR-1被认为是一种天然的血管生成抑制因子，也是癌症进展的替代标记物；它还与妊娠高血压综合征(称为先兆子痫)和正常角膜的无血管有关。选择性的mRNA剪接是否是产生sVEGFR-1的唯一机制仍是一个悬而未决的问题。在这项研究中，我们发现在白血病癌细胞中，PlGF和VEGF-A都能诱导VEGFR-1的酪氨酸磷酸化，使其易于胞外结构域的脱落，导致sVEGFR-1的产生和细胞内的胞浆片段。蛋白激酶C和肿瘤坏死因子-α转换酶家族金属蛋白酶的激活是血管内皮生长因子受体-1发生的关键。胞外结构域被去除后，VEGFR-1的残基仍然附着在细胞膜上，需要γ分泌酶/早老素的活性才能将其从细胞膜中释放出来。我们认为，通过胞外结构域剥离产生的sVEGFR-1通过作为显性-负性形式和/或与VEGF受体形成非信号二聚化复合体而拮抗VEGFR-1信号传导，从而在血管内皮生长因子受体系统中发挥重要作用。
Vascular endothelial growth factor receptor-1/fms-related tyrosine kinase 1 (VEGFR-1/FLT1) is expressed as a membrane-bound receptor tyrosine kinase and as an alternatively spliced soluble protein (sVEGFR-1) containing the 1-6 IgG-like domain of its ectodomain. sVEGFR-1 is known as a naturally occurring inhibitor of angiogenesis and as a surrogate marker for cancer progression; it is also linked to pregnancy-induced hypertension called preeclampsia and to avascularity of normal cornea. It remains an open question whether alternative mRNA splicing is the only mechanism by which sVEGFR-1 is generated. In this study, we show that in leukemic cancer cells, PlGF and VEGF-A both induce tyrosine phosphorylation of VEGFR-1 and render it susceptible to ectodomain shedding, resulting in the generation of sVEGFR-1 and an intracellular cytoplasmic fragment. Activation of protein kinase C and tumor necrosis factor-α–converting enzyme family metalloproteases are critically required for the occurrence of sVEGFR-1. Following the removal of the ectodomain, the remnant of VEGFR-1 remains attached to the membrane, and the activity of γ-secretase/presenilin is required for its release from the cell membrane. We propose that sVEGFR-1 produced via ectodomain shedding plays a prominent role in the VEGF receptor system by antagonizing VEGF receptor signaling by acting as a dominant-negative form and/or forming a nonsignaling dimerizing complex with VEGF receptors.