Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institute, Villigen, Switzerland.
Blood. 2011 Jul 21;118(3):816-26. doi: 10.1182/blood-2011-01-328773. Epub 2011 May 17.
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.
血管内皮生长因子 (VEGFs) 通过激活 3 种受体酪氨酸激酶 (RTKs)，即 VEGFR-1、-2 和 -3，以及与神经纤毛蛋白-1 (NRP-1) 等辅助受体结合，来调节血液和淋巴管的发育。我们研究了不同的 VEGF-A 同种型，特别是 VEGF-A(165)a 和 VEGF-A(165)b，如何控制 VEGFR-2 循环、降解和信号转导之间的平衡。用 NRP-1 结合的 VEGF-A(165)a 刺激细胞会导致 NRP-1 介导的 VEGFR-2 通过 Rab5、Rab4 和 Rab11 小泡进行顺序循环。循环伴随着 Rab4 和 Rab11 小泡之间 VEGFR-2 的去磷酸化，并且定量和定性地改变了信号输出。在被 VEGF-A(165)b 刺激的细胞中，VEGF-A(165)b 是一种不能与 NRP-1 结合的同种型，VEGFR-2 绕过 Rab11 小泡，并被导向由 Rab7 小泡指定的降解途径。NRP-1 的 GIPC（突触结合蛋白）结合基序的缺失阻止了 VEGFR-2 通过 Rab11 小泡的转运，并减弱了信号转导。辅助受体的结合是 VEGFR-2 特异性的，因为在没有已知辅助受体的情况下，EGFR 通过 Rab11 小泡循环。我们的数据确立了 NRP-1 在 VEGFR-2 信号中的独特作用，并揭示了辅助受体在调节 RTK 信号输出方面的一般机制。
