Flt-1, a receptor for vascular endothelial growth factor, has transforming and morphogenic potentials
Flt-1, a receptor for vascular endothelial growth factor, has transforming and morphogenic potentials
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Flt-1 是血管内皮生长因子的受体，具有转化和形态发生潜力
DOI：
10.1038/sj.onc.1201786
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发表时间：
1998
期刊：
影响因子：
8
通讯作者：
M. Shibuya
中科院分区：
文献类型：
--
作者：
Y. Maru;S. Yamaguchi;M. Shibuya
Flt-1是血管内皮生长因子（VEGF）的酪氨酸激酶受体，其矛盾之处在于配体不能激活受体以刺激外源性过表达受体的细胞的生长。为了找到Flt-1激酶依赖的生物系统，我们首次以配体非依赖性方式获得了Flt-1激酶的活化形式。将人白血病癌蛋白BCR-ABL中的ABL序列替换为Flt-1的胞质结构域（BCR-FLT），然后进行逆转录病毒随机诱变方案，得到在Flt-1序列内具有突变的组成型活性人工嵌合体BCR-FLTm。与BCR-ABL类似，它可以转化Rat 1成纤维细胞，消除Ba/F3细胞中的细胞因子依赖性，并在神经元PC 12细胞中诱导神经突样结构，但不是原始的BCR-FLT。有趣的是，BCR-FLTm转化的Rat 1细胞在基底膜基质中形成管状结构。BCR-FLTm逆转录病毒可能是研究Flt-1激酶功能的一个非常有用的工具。
A paradox of Flt-1, a tyrosine kinase receptor for vascular endothelial growth factor (VEGF), is that the ligand cannot activate the receptor to stimulate growth of cells that exogenously overexpress the receptor. In order to find Flt-1 kinase-dependent biological systems, we obtained for the first time activated forms of the Flt-1 kinase in a ligand-independent manner. Replacement of the ABL sequences in the human leukemia oncoprotein BCR–ABL with the cytoplasmic domain of Flt-1 (BCR–FLT) followed by a retroviral random mutagenesis scheme gave constitutively active artificial chimera BCR–FLTm with mutations within the Flt-1 sequence. Like BCR–ABL it could, but not the original BCR–FLT, transform Rat1 fibroblasts, abrogate cytokine dependence in Ba/F3 cells, and induce neurite-like structures in neuronal PC12 cells. Interestingly, Rat1 cells transformed by BCR–FLTm formed tube-like structures in basement membrane matrix. BCR–FLTm retroviruses may be a very useful tool to investigate an as yet uncovered functions of the Flt-1 kinase.