Department of Immunology, Genetics and Pathology, Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Dag Hammarskjöldsväg 20, 75185 Uppsala, Sweden.
Ridgeview Instruments, Skillsta 4, 740 20 Vänge, Sweden.
Dev Cell. 2014 Mar 31;28(6):633-46. doi: 10.1016/j.devcel.2014.02.010. Epub 2014 Mar 20.
Neuropilin 1 (NRP1) modulates angiogenesis by binding vascular endothelial growth factor (VEGF) and its receptor, VEGFR2. We examined the consequences when VEGFR2 and NRP1 were expressed on the same cell (cis) or on different cells (trans). In cis, VEGF induced rapid VEGFR2/NRP1 complex formation and internalization. In trans, complex formation was delayed and phosphorylation of phospholipase Cγ (PLCγ) and extracellular regulated kinase 2 (ERK2) was prolonged, whereas ERK1 phosphorylation was reduced. Trans complex formation suppressed initiation and vascularization of NRP1-expressing mouse fibrosarcoma and melanoma. Suppression in trans required high-affinity, steady-state binding of VEGF to NRP1, which was dependent on the NRP1 C-terminal domain. Compatible with a trans effect of NRP1, quiescent vasculature in the developing retina showed continuous high NRP1 expression, whereas angiogenic sprouting occurred where NRP1 levels fluctuated between adjacent endothelial cells. Therefore, through communication in trans, NRP1 can modulate VEGFR2 signaling and suppress angiogenesis.
神经纤毛蛋白 1（NRP1）通过结合血管内皮生长因子（VEGF）及其受体 VEGFR2 来调节血管生成。我们研究了当 VEGFR2 和 NRP1 表达在同一细胞（顺式）或不同细胞（反式）上时会产生什么后果。在顺式中，VEGF 诱导 VEGFR2/NRP1 复合物的快速形成和内化。在反式中，复合物的形成被延迟，PLCγ 和 ERK2 的磷酸化被延长，而 ERK1 的磷酸化被减少。反式复合物的形成抑制了 NRP1 表达的小鼠纤维肉瘤和黑色素瘤的起始和血管生成。反式抑制需要 VEGF 与 NRP1 的高亲和力、稳态结合，这依赖于 NRP1 的 C 末端结构域。与 NRP1 的反式作用一致，发育中的视网膜中的静止血管显示出持续的高 NRP1 表达，而血管生成的发芽则发生在相邻内皮细胞之间 NRP1 水平波动的地方。因此，NRP1 通过反式通讯可以调节 VEGFR2 信号并抑制血管生成。
