Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers
Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers
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DOI：
10.1074/jbc.274.45.32127
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发表时间：
1999-11-05
影响因子：
4.8
通讯作者：
Achen, MG
中科院分区：
文献类型：
--
作者：
Stacker, SA;Stenvers, K;Achen, MG
血管内皮生长因子-D（VEGF-D）结合并激活内皮细胞酪氨酸激酶受体VEGF受体-2（VEGFR-2）和VEGF受体-3（VEGFR-3），对内皮细胞具有促有丝分裂作用，并且与VEGF-C具有结构同源性和受体特异性。VEGF-D的主要翻译产物除了中心VEGF同源结构域（VHD）之外，还具有长的N-和C-末端多肽延伸。VEGF-D的VHD足以结合并激活VEGFR-2和VEGFR-3。在这里，我们报告说，VEGF-D是蛋白水解处理释放VHD。在293 EBNA细胞中的研究表明，VEGF-D经历N端和C端切割事件以产生许多分泌的多肽，包括类似于仅由VHD组成的21，000的完全加工形式的M-r，其主要是非共价二聚体。生物传感器分析表明，与未加工的VEGF-D相比，VHD对VEGFR-2和VEGFR-3的亲和力分别高出290倍和40倍。原位杂交结果表明，胚胎肺是VEGF-D基因表达的主要部位。在胚胎肺中检测到VEGF-D的加工形式，表明VEGF-D在体内被蛋白水解加工。
Vascular endothelial growth factor-D (VEGF-D) binds and activates the endothelial cell tyrosine kinase receptors VEGF receptor-2 (VEGFR-2) and VEGF receptor-3 (VEGFR-3), is mitogenic for endothelial cells, and shares structural homology and receptor specificity with VEGF-C, The primary translation product of VEGF-D has long N- and C-terminal polypeptide extensions in addition to a central VEGF homology domain (VHD). The VHD of VEGF-D is sufficient to bind and activate VEGFR-2 and VEGFR-3. Here we report that VEGF-D is proteolytically processed to release the VHD. Studies in 293EBNA cells demonstrated that VEGF-D undergoes Nand C-terminal cleavage events to produce numerous secreted polypeptides including a fully processed form of M-r similar to 21,000 consisting only of the VHD, which is predominantly a non-covalent dimer. Biosensor analysis demonstrated that the VHD has similar to 290- and similar to 40-fold greater affinity for VEGFR-2 and VEGFR-3, respectively, compared with unprocessed VEGF-D. In situ hybridization demonstrated that embryonic lung is a major site of expression of the VEGF-D gene. Processed forms of VEGF-D were detected in embryonic lung indicating that VEGF-D is proteolytically processed in vivo.