Neuropilin-1/GIPC1 signaling regulates alpha5beta1 integrin traffic and function in endothelial cells.
Neuropilin-1/GIPC1 signaling regulates alpha5beta1 integrin traffic and function in endothelial cells.
复制标题
Neuropilin-1/gipc1信号传导调节内皮细胞中α5Beta1整合素的交通和功能。
DOI：
10.1371/journal.pbio.1000025
复制
发表时间：
2009-01-27
期刊：
影响因子：
9.8
通讯作者：
Serini G
中科院分区：
文献类型：
--
作者：
Valdembri D;Caswell PT;Anderson KI;Schwarz JP;König I;Astanina E;Caccavari F;Norman JC;Humphries MJ;Bussolino F;Serini G
神经纤毛蛋白1（Nrp 1）是血管内皮生长因子A165（VEGF-A165，小鼠VEGF-A164）和脑信号蛋白3A（SEMA 3A）的共受体。然而，Nrp 1基因缺失的胚胎显示出与缺乏VEGF-A164或Sema 3A蛋白的小鼠不同的血管缺陷。此外，最近已经报道，Nrp 1是内皮细胞（EC）对VEGF-A165和VEGF-A121同种型的应答所必需的，后者不能结合EC表面上的Nrp 1。总之，这些数据表明，Nrp 1的损失所造成的血管表型可能是由于VEGF-A164/SEMA 3A的Nrp 1在内皮细胞中的独立功能，如粘附到细胞外基质。通过使用RNA干扰和野生型和突变型结构的拯救，我们在这里表明，Nrp 1通过其细胞质SEA基序，独立于VEGF-A165和SEMA 3A，特异性地促进α5β1-整合素介导的EC粘附到纤连蛋白，这对血管发育至关重要。我们提供的证据表明，Nrp 1，而不是直接介导细胞在纤连蛋白上的铺展，与α5β1在粘附位点相互作用。同源多聚体内吞衔接子GAIP相互作用蛋白C末端成员1（GIPC 1）与Nrp 1的SEA基序的结合选择性地刺激Rab 5阳性早期内体中活性α5β1的内化。因此，也与α5β1相互作用的GIPC 1和相关的运动肌球蛋白VI（Myo 6）支持活性α5β1内吞作用和EC粘附至纤连蛋白。总之，我们认为Nrp 1除了作为VEGF-A165和SEMA 3A的辅助受体之外，还通过其胞质结构域通过增加Rab 5/GIPC 1/Myo 6依赖的活性α5β1的内化来刺激内皮细胞在纤连蛋白上的扩散。Nrp 1对α5β1整合素功能的调节可能在Nrp 1缺失小鼠中观察到的血管生成缺陷的产生中起因果作用。血管系统是由内皮细胞排列的血管的分级网络，所述内皮细胞通过跨膜整合素蛋白结合到周围的蛋白质性细胞外基质（ECM）。整联蛋白是正常心血管发育所必需的，并且以弯曲（非活性）和延伸（活性）的形状存在，这些形状相应地不能并且能够附着到ECM上。细胞外引导因子，如血管内皮生长因子和信号蛋白，结合跨膜蛋白神经纤毛蛋白-1（Nrp 1），然后激活生化信号，分别激活或抑制内皮整合素。在这里，我们表明，Nrp 1，通过其短的胞质结构域和独立的血管内皮生长因子和semaphorins，特别是促进内皮细胞附着的ECM蛋白纤连蛋白，这是已知的血管发育至关重要。值得注意的是，Nrp 1通过与纤连蛋白结合的整合素结合并促进其延伸形式在内皮细胞与ECM接触之间来回的快速囊泡运输来促进细胞粘附。Nrp 1胞质结构域与衔接蛋白GIPC 1的结合也是必需的，衔接蛋白GIPC 1又与整合素内化和囊泡运动所需的蛋白质相关联。这是可能的，这样的整合素跑步机可以作为一个主要的调节细胞粘附一般。跨膜蛋白neuropilin-1通过增强在细胞粘附位点的活性整合素介导来促进内皮细胞与细胞外基质的粘附。
Neuropilin 1 (Nrp1) is a coreceptor for vascular endothelial growth factor A165 (VEGF-A165, VEGF-A164 in mice) and semaphorin 3A (SEMA3A). Nevertheless, Nrp1 null embryos display vascular defects that differ from those of mice lacking either VEGF-A164 or Sema3A proteins. Furthermore, it has been recently reported that Nrp1 is required for endothelial cell (EC) response to both VEGF-A165 and VEGF-A121 isoforms, the latter being incapable of binding Nrp1 on the EC surface. Taken together, these data suggest that the vascular phenotype caused by the loss of Nrp1 could be due to a VEGF-A164/SEMA3A-independent function of Nrp1 in ECs, such as adhesion to the extracellular matrix. By using RNA interference and rescue with wild-type and mutant constructs, we show here that Nrp1 through its cytoplasmic SEA motif and independently of VEGF-A165 and SEMA3A specifically promotes α5β1-integrin-mediated EC adhesion to fibronectin that is crucial for vascular development. We provide evidence that Nrp1, while not directly mediating cell spreading on fibronectin, interacts with α5β1 at adhesion sites. Binding of the homomultimeric endocytic adaptor GAIP interacting protein C terminus, member 1 (GIPC1), to the SEA motif of Nrp1 selectively stimulates the internalization of active α5β1 in Rab5-positive early endosomes. Accordingly, GIPC1, which also interacts with α5β1, and the associated motor myosin VI (Myo6) support active α5β1 endocytosis and EC adhesion to fibronectin. In conclusion, we propose that Nrp1, in addition to and independently of its role as coreceptor for VEGF-A165 and SEMA3A, stimulates through its cytoplasmic domain the spreading of ECs on fibronectin by increasing the Rab5/GIPC1/Myo6-dependent internalization of active α5β1. Nrp1 modulation of α5β1 integrin function can play a causal role in the generation of angiogenesis defects observed in Nrp1 null mice. The vascular system is a hierarchical network of blood vessels lined by endothelial cells that, by means of the transmembrane integrin proteins, bind to the surrounding proteinaceous extracellular matrix (ECM). Integrins are required for proper cardiovascular development and exist in bent (inactive) and extended (active) shapes that are correspondingly unable and able to attach to the ECM. Extracellular guidance cues, such as vascular endothelial growth factor and semaphorins, bind the transmembrane protein neuropilin-1 (Nrp1) and then activate biochemical signals that, respectively, activate or inactivate endothelial integrins. Here, we show that Nrp1, via its short cytoplasmic domain and independently of vascular endothelial growth factor and semaphorins, specifically promotes endothelial cell attachment to the ECM protein fibronectin, which is known to be crucial for vascular development. Notably, Nrp1 favors cell adhesion by associating with fibronectin-binding integrins and promoting the fast vesicular traffic of their extended form back and forth from the endothelial cell-to-ECM contacts. Binding of the Nrp1 cytoplasmic domain with the adaptor protein GIPC1, which in turn associates with proteins required for integrin internalization and vesicle motility, is required as well. It is likely that such an integrin treadmill could act as a major regulator of cell adhesion in general. The transmembrane protein neuropilin-1 promotes endothelial cell attachment to the extracellular matrix by enhancing active integrin treadmilling at cell-adhesion sites.
登录
查看更多内容
影响因子：
10.4
作者：
Hynes, R. O.
通讯作者：
Hynes, R. O.
影响因子：
11.8
作者：
Chittenden, Thomas W.;Claes, Filip;Simons, Michael
通讯作者：
Simons, Michael
影响因子：
21.3
作者：
Ezratty, EJ;Partridge, MA;Gundersen, GG
通讯作者：
Gundersen, GG
影响因子：
4.8
作者：
Guttmann-Raviv, Noga;Shraga-Heled, Niva;Neufeld, Gera
通讯作者：
Neufeld, Gera
影响因子：
11.8
作者：
Gu, CH;Rodriguez, ER;Ginty, DD
通讯作者：
Ginty, DD