Multiple forms of mouse vascular endothelial growth factor-D are generated by RNA splicing and proteolysis
Multiple forms of mouse vascular endothelial growth factor-D are generated by RNA splicing and proteolysis
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DOI：
10.1074/jbc.m106188200
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发表时间：
2001-11-23
影响因子：
4.8
通讯作者：
Achen, MG
中科院分区：
文献类型：
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作者：
Baldwin, ME;Roufail, S;Achen, MG
分泌的糖蛋白血管内皮生长因子-D（VEGF-D）是血管生成的、淋巴管生成的，并且促进肿瘤细胞通过淋巴管的转移性扩散。VEGF-D由受体结合结构域（VEGF同源结构域）和N-和G末端前肽组成。蛋白水解加工产生多种形式的人VEGF-D，包括完全加工的衍生物（仅含有VEGF同源结构域）、部分加工的衍生物和未加工的衍生物。蛋白水解对于产生以高亲和力结合血管生成受体VEGF受体-2（VEGFR-2）和淋巴管生成受体VEGFR-3的人VEGF-D是必需的。在这里，我们报告说，在小鼠VEGF-D基因的外显子6中的RNA剪接供体位点的替代使用产生两种不同的蛋白质亚型，VEGF-D-358和VEGF-D-326，具有不同的C末端。这两种异构体都在所有成年小鼠组织中表达，并分析了胚胎发育阶段。两种亚型均以与人VEGF-D相似的方式进行蛋白水解加工，以产生一系列分泌衍生物，并以相似的效力结合和交联VEGFR-3。当在体外表达时，同种型被不同地糖基化。这项研究表明，RNA剪接，蛋白质糖基化和蛋白水解是产生小鼠VEGF-D结构多样性的机制。
The secreted glycoprotein vascular endothelial growth factor-D (VEGF-D) is angiogenic, lymphangiogenic, and promotes metastatic spread of tumor cells via lymphatic vessels. VEGF-D consists of a receptor-binding domain (VEGF homology domain) and N- and G terminal propeptides. Proteolytic processing produces numerous forms of human VEGF-D, including fully processed derivatives (containing only the VEGF homology domain), partially processed, and unprocessed derivatives. Proteolysis is essential to generate human VEGF-D that binds the angiogenic receptor VEGF receptor-2 (VEGFR-2) and the lymphangiogenic receptor VEGFR-3 with high affinity. Here, we report that alternative use of an RNA splice donor site in exon 6 of the mouse VEGF-D gene produces two different protein isoforms, VEGF-D-358 and VEGF-D-326, with distinct C termini. The two isoforms were both expressed in all adult mouse tissues and embryonic stages of development analyzed. Both isoforms are proteolytically processed in a similar fashion to human VEGF-D to generate a range of secreted derivatives and bind and cross-link VEGFR-3 with similar potency. The isoforms are differently glycosylated when expressed in vitro. This study demonstrates that RNA splicing, protein glycosylation, and proteolysis are mechanisms for generating structural diversity of mouse VEGF-D.