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首页> 外文期刊>Molecular biology of the cell >Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin
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Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin

机译：ErbB2的内吞作用和分选以及癌症治疗药物曲妥珠单抗和格尔德霉素的作用位点

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ErbB2 is a transmembrane tyrosine kinase whose surface overexpression is linked to tumorigenesis and poor prognosis in breast cancer patients. Two models have emerged that account for the high surface distribution of ErbB2. In one model, the surface pool is dynamic and governed by a balance between endocytosis and recycling, whereas in the other it is retained, static, and excluded from endocytosis. These models have contrasting implications for how ErbB2 exerts its biological function and how cancer therapies might down-regulate surface ErbB2, such as the antibody trastuzumab (Herceptin) or the Hsp90 inhibitor geldanamycin. Little is known, however, about how these treatments affect ErbB2 endocytic trafficking. To investigate this issue, we examined breast carcinoma cells by immunofluorescence and quantitative immunoelectron microscopy and developed imaging and trafficking kinetics assays using cell surface fluorescence quenching. Surprisingly, trastuzumab does not influence ErbB2 distribution but instead recycles passively with internalized ErbB2. By contrast, geldanamycin down-regulates surface ErbB2 through improved degradative sorting in endosomes exclusively rather than through increased endocytosis. These results reveal substantial dynamism in the surface ErbB2 pool and clearly demonstrate the significance of endosomal sorting in the maintenance of ErbB2 surface distribution, a critical feature of its biological function.
机译：ErbB2是一种跨膜酪氨酸激酶，其表面过表达与乳腺癌患者的肿瘤发生和不良预后有关。已经出现了两个模型，它们解释了ErbB2的高表面分布。在一个模型中，表面池是动态的，并受内吞作用和回收利用之间的平衡支配，而在另一种模型中，表面池则保持不变，静止并从内吞作用中排除。这些模型对于ErbB2如何发挥其生物学功能以及癌症疗法如何下调表面ErbB2（例如抗体曲妥珠单抗（赫赛汀）或Hsp90抑制剂格尔德霉素）具有相反的含义。然而，关于这些治疗如何影响ErbB2内吞运输的知之甚少。为了研究这个问题，我们通过免疫荧光和定量免疫电子显微镜检查了乳腺癌细胞，并利用细胞表面荧光淬灭技术开发了成像和运输动力学测定法。出人意料的是，曲妥珠单抗不影响ErbB2的分布，而是与内部化的ErbB2被动地循环利用。相比之下，格尔德霉素仅通过改善内体中的降解分类而不是通过增加内吞作用来下调表面ErbB2。这些结果揭示了表面ErbB2池中的显着活力，并清楚地证明了内体分选对维持ErbB2表面分布（其生物学功能的关键特征）的重要性。

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