The Mysterious Ways of ErbB2/HER2 Trafficking.
The Mysterious Ways of ErbB2/HER2 Trafficking.
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DOI：
10.3390/membranes4030424
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发表时间：
2014-08-06
期刊：
影响因子：
4.2
通讯作者：
Stang E
中科院分区：
文献类型：
--
作者：
Bertelsen V;Stang E
EGFR或ErbB受体酪氨酸激酶家族由EGFR/ErbB 1、ErbB 2/HER 2、ErbB 3/HER 3和ErbB 4/HER 4组成。受体活化和下游信号传导通常在质膜处的配体诱导的受体同源二聚化或异源二聚化后启动，并且内吞作用和细胞内膜转运对于信号传导结果的调节至关重要。在这些受体中，ErbB 2在几个方面是特殊的。与其他人不同，ErbB 2没有已知的配体，但仍然是最受欢迎的二聚化伴侣。此外，虽然其他受体在组成性或配体结合时下调，但ErbB 2对下调具有抗性，并且还抑制其伴侣在异源二聚化时的下调。ErbB 2抵抗下调的原因是争论的主题。与其他ErbB蛋白相反，成熟ErbB 2需要Hsp 90作为伴侣。一些数据表明，热休克蛋白90是一个重要的调节因子，如ErbB 2的稳定性，二聚化和/或信号。Hsp 90抑制剂诱导ErbB 2降解，但Hsp 90是否直接使ErbB 2内吞抵抗尚不清楚。暴露于抗ErbB 2抗体也可诱导ErbB 2的下调。由Hsp 90抑制剂或抗体诱导的下调至少部分涉及内化和内体分选至溶酶体用于降解，但也报道了逆行运输至细胞核。在这篇综述中，我们将讨论不同的分子机制，建议是重要的，使ErbB 2抗下调，并审查如何参与膜贩运时，下调和/或重新定位的ErbB 2诱导。
The EGFR- or ErbB-family of receptor tyrosine kinases consists of EGFR/ErbB1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4. Receptor activation and downstream signaling are generally initiated upon ligand-induced receptor homo- or heterodimerization at the plasma membrane, and endocytosis and intracellular membrane transport are crucial for regulation of the signaling outcome. Among the receptors, ErbB2 is special in several ways. Unlike the others, ErbB2 has no known ligand, but is still the favored dimerization partner. Furthermore, while the other receptors are down-regulated either constitutively or upon ligand-binding, ErbB2 is resistant to down-regulation, and also inhibits down-regulation of its partner upon heterodimerization. The reason(s) why ErbB2 is resistant to down-regulation are the subject of debate. Contrary to other ErbB-proteins, mature ErbB2 needs Hsp90 as chaperone. Several data suggest that Hsp90 is an important regulator of factors like ErbB2 stability, dimerization and/or signaling. Hsp90 inhibitors induce degradation of ErbB2, but whether Hsp90 directly makes ErbB2 endocytosis resistant is unclear. Exposure to anti-ErbB2 antibodies can also induce down-regulation of ErbB2. Down-regulation induced by Hsp90 inhibitors or antibodies does at least partly involve internalization and endosomal sorting to lysosomes for degradation, but also retrograde trafficking to the nucleus has been reported. In this review, we will discuss different molecular mechanisms suggested to be important for making ErbB2 resistant to down-regulation, and review how membrane trafficking is involved when down-regulation and/or relocalization of ErbB2 is induced.