The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis.
The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis.
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DOI：
10.1016/j.devcel.2013.03.019
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发表时间：
2013-04-29
影响因子：
11.8
通讯作者：
Simons, Michael
中科院分区：
文献类型：
--
作者：
Lanahan, Anthony;Zhang, Xi;Fantin, Alessandro;Zhuang, Zhen;Rivera-Molina, Felix;Speichinger, Katherine;Prahst, Claudia;Zhang, Jiasheng;Wang, Yingdi;Davis, George;Toomre, Derek;Ruhrberg, Christiana;Simons, Michael
神经粘连蛋白1(Nrp1)在血管内皮细胞生长因子-A信号转导和血管形态发生中起重要作用，但作用不明确。我们发现，带有敲门基因突变的Nrp1胞浆尾巴(Nrp1cyto)的小鼠有正常的血管生成，但发育和成年动脉生成受损。动脉形成缺陷是由于Nrp1和血管内皮生长因子受体2(VEGFR2)复合体和连接素之间缺乏依赖PDZ的相互作用，从而延迟了内吞的VEGFR2从Rab5+到EAA1+的转运。这导致PTPN1(PTP1B)介导的VEGFR2在Y1175的去磷酸化增加，Y1175是参与激活ERK信号的位置。Nrp1细胞突变也损害了体外培养的内皮细胞的小管生成，这可以通过表达全长Nrp1或结构性激活的ERK来挽救。这些结果表明，Nrp1胞浆结构域以PDZ依赖的方式促进VEGFR2的运输，从而调节动脉源性ERK信号，并确立Nrp1在血管形态发生过程中对VEGF-A信号的作用。Nrp1胞浆结构域在缺失的情况下促进血管内皮生长因子受体(VEGFR)2的胞内转运，VEGR2转运在分选内小体时延迟，PTP1B与Rab5+分选内小体结合并使VEGFR2的Y1175位去磷酸化。研究发现，血管内皮生长因子辅助受体Nrp1是血管内皮细胞生长因子2内向转运所必需的。在缺乏Nrp1‘S胞浆结构域的敲门小鼠中，VEGFR2通过早期内吞隔室的速度较慢，增加了其对抑制性磷酸酶PTP1B的暴露，并减弱了血管内皮生长因子刺激的ERK信号转导和动脉形成。
Neuropilin 1 (NRP1) plays an important but ill-defined role in VEGF-A signaling and vascular morphogenesis. We show that mice with a knockin mutation that ablates the NRP1 cytoplasmic tail (Nrp1cyto) have normal angiogenesis but impaired developmental and adult arteriogenesis. The arteriogenic defect was traced to the absence of a PDZ-dependent interaction between NRP1 and VEGF receptor 2 (VEGFR2) complex and synectin, which delayed trafficking of endocytosed VEGFR2 from Rab5+ to EAA1+ endosomes. This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y1175, the site involved in activating ERK signaling. The Nrp1cyto mutation also impaired endothelial tubulogenesis in vitro, which could be rescued by expressing full-length NRP1 or constitutively active ERK. These results demonstrate that the NRP1 cytoplasmic domain promotes VEGFR2 trafficking in a PDZ-dependent manner to regulate arteriogenic ERK signaling and establish a role for NRP1 in VEGF-A signaling during vascular morphogenesis. The NRP1 cytoplasmic domain promotes VEGF receptor (VEGFR) 2 endocytic trafficking In its absence, VEGR2 trafficking is delayed in sorting endosomes PTP1b binds to Rab5+ sorting endosomes and dephosphorylates the Y1175 site of VEGFR2 Loss of the NRP1 cytoplasmic domain impairs developmental and adult arteriogenesis Lanahan et al. find that the VEGF coreceptor NRP1 is required for proper VEGFR2 endocytic trafficking. In knockin mice lacking NRP1’s cytoplasmic domain, VEGFR2 passes through early endocytic compartments more slowly, increasing its exposure to the inhibitory phosphatase PTP1b and attenuating VEGF-stimulated ERK signaling and arteriogenesis.
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影响因子：
3.9
作者：
Koch, Sina
通讯作者：
Koch, Sina
影响因子：
11.8
作者：
Lanahan, Anthony A.;Hermans, Karlien;Claes, Filip;Kerley-Hamilton, Joanna S.;Zhuang, Zhen W.;Giordano, Frank J.;Carmeliet, Peter;Simons, Michael
通讯作者：
Simons, Michael
影响因子：
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作者：
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通讯作者：
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分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
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通过膜流量调节VEGF信号。
影响因子：
4.8
作者：
Horowitz A;Seerapu HR
通讯作者：
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