Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output
Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output
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DOI：
10.1182/blood-2011-01-328773
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发表时间：
2011-07-21
期刊：
影响因子：
20.3
通讯作者：
Berger, Philipp
中科院分区：
文献类型：
--
作者：
Ballmer-Hofer, Kurt;Andersson, Anneli E.;Berger, Philipp
血管内皮生长因子(VEGFs)通过激活3种受体酪氨酸激酶(RTKs)、VEGFR-1、-2和-3，并与辅助受体如神经粘蛋白-1(NRP-1)结合，调节血管和淋巴管的发育。我们研究了不同的血管内皮生长因子-A亚型，特别是血管内皮生长因子-A(165)a和血管内皮生长因子-A(165)b，如何控制VEGFR-2的循环、降解和信号之间的平衡。用NRP-1结合的VEGF-A(165)刺激细胞，导致NRP-1介导的VEGFR-2通过Rab5、Rab4和Rab11囊泡依次循环。再循环伴随着VEGFR-2在Rab4和Rab11囊泡之间的去磷酸化，并在数量和质量上改变了信号输出。在VEGF-A(165)b刺激的细胞中，VEGFR-2绕过Rab11小泡，进入Rab7小泡指定的降解途径，这是一个不能结合NRP-1的异构体。NRP-1的GIPC(连接素)结合基序的缺失阻止了VEGFR-2通过Rab11小泡的转移和信号减弱。共受体结合是VEGFR-2所特有的，因为在缺乏已知辅助受体的情况下，EGFR通过Rab11囊泡循环。我们的数据确立了NRP-1在VEGFR-2信号中的独特作用，并揭示了辅助受体调节RTK信号输出的一般机制。(血。2011；118(3)：816-826)
Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development by activating 3 receptor tyrosine kinases (RTKs), VEGFR-1, -2, and -3, and by binding to coreceptors such as neuropilin-1 (NRP-1). We investigated how different VEGF-A isoforms, in particular VEGF-A(165)a and VEGF-A(165)b, control the balance between VEGFR-2 recycling, degradation, and signaling. Stimulation of cells with the NRP-1-binding VEGF-A(165)a led to sequential NRP-1-mediated VEGFR-2 recycling through Rab5, Rab4, and Rab11 vesicles. Recycling was accompanied by dephosphorylation of VEGFR-2 between Rab4 and Rab11 vesicles and quantitatively and qualitatively altered signal output. In cells stimulated with VEGF-A(165)b, an isoform unable to bind NRP-1, VEGFR-2 bypassed Rab11 vesicles and was routed to the degradative pathway specified by Rab7 vesicles. Deletion of the GIPC (synectin) binding motif of NRP-1 prevented transition of VEGFR-2 through Rab11 vesicles and attenuated signaling. Coreceptor engagement was specific for VEGFR-2 because EGFR recycled through Rab11 vesicles in the absence of known coreceptors. Our data establish a distinct role of NRP-1 in VEGFR-2 signaling and reveal a general mechanism for the function of coreceptors in modulating RTK signal output. (Blood. 2011;118(3):816-826)