Pedersen Nina Marie, Madshus Inger Helene, Haslekås Camilla, Stang Espen
Institute of Pathology, University of Oslo Faculty of Medicine, Oslo, Norway.
Mol Cancer Res. 2008 Mar;6(3):491-500. doi: 10.1158/1541-7786.MCR-07-0191.
ErbB2, a member of the epidermal growth factor receptor family, is overexpressed in a number of human cancers. In contrast to the epidermal growth factor receptor, ErbB2 is normally endocytosis resistant. However, ErbB2 can be down-regulated by inhibitors of heat shock protein 90, such as geldanamycin. We now show that geldanamycin induces endocytosis and lysosomal degradation of full-length ErbB2. We further report that the endocytosis of ErbB2 is dynamin and clathrin dependent. When ErbB2 was retained at the plasma membrane due to knockdown of clathrin heavy chain, the intracellular part of ErbB2 was degraded in a proteasomal manner. However, our data strongly suggest that proteasomal activity is not required for geldanamycin-induced endocytosis of ErbB2 in SKBr3 cells. Interestingly, however, proteasomal inhibitors retarded degradation of ErbB2, and electron microscopy analysis strongly suggested that proteasomal activity is required to sort internalized ErbB2 to lysosomes. Because geldanamycin derivatives and inhibitors of proteasomal activity are both used in experimental cancer treatment, knowledge of molecular mechanisms involved in geldanamycin-induced down-regulation of ErbB2 is important for future design of cancer treatment.
表皮生长因子受体家族成员ErbB2在多种人类癌症中过度表达。与表皮生长因子受体不同，ErbB2通常具有抗内吞作用。然而，ErbB2可被热休克蛋白90抑制剂（如格尔德霉素）下调。我们现在表明，格尔德霉素可诱导全长ErbB2的内吞作用和溶酶体降解。我们进一步报告，ErbB2的内吞作用依赖于发动蛋白和网格蛋白。当由于网格蛋白重链的敲低而使ErbB2保留在质膜上时，ErbB2的细胞内部分以蛋白酶体方式降解。然而，我们的数据强烈表明，蛋白酶体活性对于格尔德霉素诱导的SKBr3细胞中ErbB2的内吞作用并非必需。然而，有趣的是，蛋白酶体抑制剂延缓了ErbB2的降解，电子显微镜分析强烈表明，蛋白酶体活性是将内化的ErbB2分选到溶酶体所必需的。由于格尔德霉素衍生物和蛋白酶体活性抑制剂都用于实验性癌症治疗，了解格尔德霉素诱导的ErbB2下调所涉及的分子机制对于未来癌症治疗的设计很重要。
