Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling
Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling
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DOI：
10.1038/sj.emboj.7601188
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发表时间：
2006-07-12
期刊：
影响因子：
11.4
通讯作者：
Hori, Masatsugu
中科院分区：
文献类型：
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作者：
Shintani, Yasunori;Takashima, Seiji;Hori, Masatsugu
神经毛细蛋白-1(Nrp1)是血管内皮生长因子(VEGF)的共同受体，与VEGFR2协同增强血管生成信号。血管内皮生长因子信号转导通路通过作用于血管内皮细胞和平滑肌细胞，对生理性和病理性血管生成起着至关重要的作用，但其作用机制尚不清楚。在这里，我们证明了Nrp1的相当一部分是用硫酸肝素或硫酸软骨素修饰的蛋白多糖在单个保守的Ser上。Nrp1糖胺聚糖(GAG)链的组成在ECs和SMC之间是不同的。糖基化增加了两种细胞中的血管内皮生长因子结合，但Nrp1不同的GAG组成在内皮细胞和平滑肌细胞中介导了对血管内皮生长因子的相反反应。最后，Nrp1的表达及其GAG修饰在转录后调控VEGFR2蛋白的表达。这些发现表明，Nrp1的GAG修饰在调节血管内皮生长因子信号通路中起着关键作用，并可能为生理和病理血管生成提供新的见解。
Neuropilin-1 (NRP1) is a co-receptor for vascular endothelial growth factor (VEGF) that enhances the angiogenic signals cooperatively with VEGFR2. VEGF signaling is essential for physiological and pathological angiogenesis through its effects on vascular endothelial cells (ECs) and smooth muscle cells (SMCs), but the mechanisms coordinating this response are not well understood. Here we show that a substantial fraction of NRP1 is proteoglycan modified with either heparan sulfate or chondroitin sulfate on a single conserved Ser. The composition of the NRP1 glycosaminoglycan (GAG) chains differs between ECs and SMCs. Glycosylation increased VEGF binding in both cell types, but the differential GAG composition of NRP1 mediates opposite responsiveness to VEGF in ECs and SMCs. Finally, NRP1 expression and its GAG modification post-transcriptionally regulate VEGFR2 protein expression. These findings indicate that GAG modification of NRP1 plays a critical role in modulating VEGF signaling, and may provide new insights into physiological and pathological angiogenesis.