VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis.
VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis.
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DOI：
10.1242/bio.017434
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发表时间：
2016-05-15
期刊：
影响因子：
2.4
通讯作者：
Ponnambalam S
中科院分区：
文献类型：
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作者：
Fearnley GW;Smith GA;Abdul-Zani I;Yuldasheva N;Mughal NA;Homer-Vanniasinkam S;Kearney MT;Zachary IC;Tomlinson DC;Harrison MA;Wheatcroft SB;Ponnambalam S
血管内皮生长因子A（VEGF-A）与受体酪氨酸激酶VEGFR 2结合，触发多种信号转导途径，调节控制血管发育的内皮细胞反应。VEGF-A的多种异构体可以引起不同的信号转导和内皮反应。然而，目前还不清楚这种细胞反应是如何通过亚型特异性VEGF-A-VEGFR 2复合物控制的。越来越多的人认识到受体-配体复合物的膜运输影响信号转导和蛋白质周转。通过建立在这些概念上，我们的研究首次表明，三种不同的VEGF-A亚型（VEGF-A165，VEGF-A121和VEGF-A145）促进了VEGFR 2内吞作用的不同模式，以递送到早期内体中。这种差异性VEGFR 2内吞作用和运输与VEGF-A亚型特异性信号转导事件有关。网格蛋白依赖性内吞作用的破坏阻断了VEGF-A亚型特异性VEGFR 2的激活、信号转导，并导致膜结合VEGFR 1和VEGFR 2水平的大量耗竭。此外，这种VEGF-A亚型促进VEGFR 2泛素化、蛋白水解和末端降解的差异模式。我们的研究现在为不同的VEGF-A亚型如何结合相同的受体酪氨酸激酶并引发不同的细胞结果提供了新的见解。总结：我们发现，血管内皮生长因子（VEGF-A）亚型程序差异酪氨酸磷酸化，泛素化，内吞和受体酪氨酸激酶，VEGFR 2的蛋白水解。
Vascular endothelial growth factor A (VEGF-A) binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A–VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor–ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145) promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes. Summary: We show that vascular endothelial growth factor (VEGF-A) isoforms program differential tyrosine phosphorylation, ubiquitylation, endocytosis and proteolysis of the receptor tyrosine kinase, VEGFR2.