Gampel Alexandra, Moss Lara, Jones Matt C, Brunton Val, Norman Jim C, Mellor Harry
Mammalian Cell Biology Laboratory, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
Blood. 2006 Oct 15;108(8):2624-31. doi: 10.1182/blood-2005-12-007484. Epub 2006 Apr 25.
Endothelial cells respond to vascular endothelial growth factor (VEGF) to produce new blood vessels. This process of angiogenesis makes a critical contribution during embryogenesis and also in the response to ischemia in adult tissues. We have studied the intracellular trafficking of the major VEGF receptor KDR (VEGFR2). Unlike other related growth factor receptors, we find that a significant proportion of KDR is held in an endosomal storage pool within endothelial cells. We find that KDR can be delivered to the plasma membrane from this intracellular pool and that VEGF stimulates this recycling to the cell surface. KDR recycling appears to be distinct from the previously characterized Rab4- and Rab11-dependent pathways, but, instead, KDR(+) recycling vesicles contain Src tyrosine kinase and VEGF-stimulated recycling requires Src activation. Taken together, these data show that intracellular trafficking of KDR is markedly different from other receptor tyrosine kinases and suggest that the regulation of KDR trafficking by VEGF provides a novel mechanism for controlling the sensitivity of endothelial cells to proangiogenic signals.
内皮细胞对血管内皮生长因子（VEGF）作出反应以生成新血管。血管生成这一过程在胚胎发育期间以及成年组织对局部缺血的反应中都起着关键作用。我们研究了主要的VEGF受体KDR（VEGFR2）的细胞内运输。与其他相关生长因子受体不同，我们发现相当一部分KDR存在于内皮细胞内的内体储存池中。我们发现KDR可以从这个细胞内池转运到质膜，并且VEGF刺激这种向细胞表面的再循环。KDR的再循环似乎与先前表征的Rab4和Rab11依赖性途径不同，相反，KDR（+）再循环囊泡含有Src酪氨酸激酶，并且VEGF刺激的再循环需要Src激活。综上所述，这些数据表明KDR的细胞内运输与其他受体酪氨酸激酶明显不同，并表明VEGF对KDR运输的调节为控制内皮细胞对促血管生成信号的敏感性提供了一种新机制。
