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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Role of endocytosis in the activation of the extracellular signal-regulated kinase cascade hy sequestering and nonsequestering G protein-coupled receptors
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Role of endocytosis in the activation of the extracellular signal-regulated kinase cascade hy sequestering and nonsequestering G protein-coupled receptors

机译：内吞作用在激活细胞外信号调节激酶级联的隔离和非隔离G蛋白偶联受体中的作用

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Acting through a number of distinct pathways, many G protein- coupled receptors (GPCRs) activate the extracellular signal-regu- lated kinase (ERK)/mitogen-activated protein kinase (MAPK) cas- lade. Recently. it has been shown that in some cases, clathrin- mediated endocytosis is required for GPCR activation of the ERK/MAPK cascade, whereas in others it is not. Accordingly, we c0mpared ERK activation mediated by a GPCR that does not undergo agonist-stimulated endocytosis, the α2A adrenergic recep- tor , with ERK activation mediated by the β2 adrenergic receptor . which is endocytosed. Surprisingly, we found that in COS-7 cells, ERK activation by the α_2A AR, like that mediated by hoth the β_2 AR and the epidermal growth factor receptor (EGFR), is sensitive to mechanistically distinct inhibitors of clathrin-medi- ated endocytosis, including monodansylcadaverine. a mutant dy- namin I, and a mutant p-arrestin 1. Moreover, we determined that. as has been shown for many other GPCRs, both α_2A and β_2 AR-mediated ERK activation involves transactivation of the EGFR. Using confocal immunofIuorescence microscopy. we found that stimulation of the β_2 AR. the α_2A AR, or the EGFR each results in internalization of a green fluorescent protein-tagged EGFR. Al- though β_2 AR stimulation leads to redistribution of both the β_2 AR and EGFR, activation of the α_2A AR leads to redistribution of the EGFR but the α_2A AR remains on the plasma membrane. These findings separate GPCR endocytosis from the requirement for dathrin-mediated endocytosis in EGFR transactivation-mediated ERK aCtivation and suggest that it is the receptor tyrosine kinase or another downstream effector that must engage the endocytic machinery.
机译：通过许多不同的途径，许多G蛋白偶联受体（GPCR）激活细胞外信号调节激酶（ERK）/丝裂原活化蛋白激酶（MAPK）级联。最近。已经显示，在某些情况下，网格蛋白介导的内吞作用是ERK / MAPK级联反应的GPCR激活所必需的，而在其他情况下则不需要。因此，我们将不经过激动剂刺激的内吞作用即α2A肾上腺素能受体的GPCR介导的ERK活化与由β2肾上腺素能受体介导的ERK活化进行了比较。被内吞。令人惊讶的是，我们发现在COS-7细胞中，由α_2AAR激活的ERK像由β_2AR和表皮生长因子受体（EGFR）介导的激活一样，对由网格蛋白介导的内吞作用的机制独特的抑制剂敏感，包括monodansylcadaverine。突变体动力蛋白I和突变体p-arrestin1。此外，我们确定了这一点。如许多其他GPCR所示，α_2A和β_2AR介导的ERK激活均涉及EGFR的反式激活。使用共聚焦免疫荧光显微镜。我们发现刺激了β_2AR。 α_2AAR或EGFR各自导致绿色荧光蛋白标记的EGFR的内在化。尽管β_2AR刺激导致β_2AR和EGFR的重新分布，但是α_2AAR的激活导致EGFR的重新分布，但α_2AAR保留在质膜上。这些发现将GPCR内吞作用与EGFR反式激活介导的ERK活性中对黄豆素介导的内吞作用的需求分开，并表明受体酪氨酸激酶或其他下游效应子必须参与内吞机制。

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