Functional interaction of VEGF-C and VEGF-D with neuropilin receptors
Functional interaction of VEGF-C and VEGF-D with neuropilin receptors
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DOI：
10.1096/fj.05-5646com
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发表时间：
2006-07-01
期刊：
影响因子：
4.8
通讯作者：
Alitalo, Kari
中科院分区：
文献类型：
--
作者：
Karpanen, Terhi;Heckman, Caroline A.;Alitalo, Kari
淋巴管的发育受血管内皮生长因子受体3（VEGFR-3）的调节，VEGFR-3由其配体VEGF-C和VEGF-D激活。已知参与神经元发育的神经纤毛蛋白-2（NP 2）也被认为在淋巴管生成中起作用。我们的目的是阐明NP 2参与淋巴管内皮细胞信号传导的机制。通过体外结合研究，我们发现VEGF-C和VEGF-D都与NP 2相互作用，VEGF-C以肝素非依赖性方式相互作用，VEGF-D以肝素依赖性方式相互作用。我们还绘制了VEGF-C和NP 2结合所需的结构域。在用VEGF-C或VEGF-D刺激后，NP 2沿着VEGFR-3在淋巴管内皮细胞的内吞囊泡中的共内化证明了NP 2与淋巴管生成生长因子相互作用的功能重要性。在共沉淀研究中，NP 2也与VEGFR-3相互作用。我们的研究结果表明，NP 2直接参与了一个积极的信号传导复合物与淋巴管生成的关键调节，从而提出了一种机制，NP 2的功能，在发展中的淋巴管。
Lymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by its ligands VEGF-C and VEGF-D. Neuropilin-2 (NP2), known to be involved in neuronal development, has also been implicated to play a role in lymphangiogenesis. We aimed to elucidate the mechanism by which NP2 is involved in lymphatic endothelial cell signaling. By in vitro binding studies we found that both VEGF-C and VEGF-D interact with NP2, VEGF-C in a heparin-independent and VEGF-D in a heparin-dependent manner. We also mapped the domains of VEGF-C and NP2 required for their binding. The functional importance of the interaction of NP2 with the lymphangiogenic growth factors was demonstrated by cointernalization of NP2 along with VEGFR-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with VEGF-C or VEGF-D. NP2 also interacted with VEGFR-3 in coprecipitation studies. Our results show that NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis and thus suggest a mechanism by which NP2 functions in the development of the lymphatic vasculature.