Endosomal transport of ErbB-2: Mechanism for nuclear entry of the cell surface receptor
Endosomal transport of ErbB-2: Mechanism for nuclear entry of the cell surface receptor
复制标题
DOI：
10.1128/mcb.25.24.11005-11018.2005
复制
发表时间：
2005-12-01
影响因子：
5.3
通讯作者：
Hung, MC
中科院分区：
文献类型：
--
作者：
Giri, DK;Ali-Seyed, M;Hung, MC
细胞膜受体ErbB-2迁移到细胞核。然而，其核转位的机制尚不清楚。在这里，我们报告了一种新的机制，其核定位，涉及相互作用的转运受体importin β 1，核孔蛋白Nup 358，和一个主机的球员内吞内化。使用小干扰RNA寡核苷酸敲低importin β 1或通过Ran的显性阴性突变体RanQ 69 L使小GTdR Ran失活，导致ErbB-2的核转运缺陷。ErbB-2中假定的核定位信号的突变破坏了其与输入蛋白β 1的相互作用并阻止了核转位，而核输出受体的失活使ErbB-2在核内堆积。此外，阻断内化的显性负突变的发动蛋白停止其核定位。因此，细胞膜包埋的ErbB-2通过使用内吞囊泡作为媒介物、输入蛋白β 1作为驱动剂和Nup 358作为交通灯的内吞作用，从细胞表面迁移到细胞核。这种新的机制解释了细胞表面的受体酪氨酸激酶如何转移到细胞核中。这条通路可能作为一种通用机制，允许细胞表面受体和细胞核之间的直接通信，因此，我们的研究结果打开了一个新时代，了解细胞膜和细胞核之间的直接运输。
The cell membrane receptor ErbB-2 migrates to the nucleus. However, the mechanism of its nuclear translocation is unclear. Here, we report a novel mechanism of its nuclear localization that involves interaction with the transport receptor importin beta 1, nuclear pore protein Nup358, and a host of players in endocytic internalization. Knocking down importin beta 1 using small interfering RNA oligonucleotides or inactivation of small GTPase Ran by RanQ69L, a dominant-negative mutant of Ran, causes a nuclear transport defect of ErbB-2. Mutation of a putative nuclear localization signal in ErbB-2 destroys its interaction with importin beta 1 and arrests nuclear translocation, while inactivation of nuclear export receptor piles up ErbB-2 within the nucleus. Additionally, blocking of internalization by a dominant-negative mutant of dynamin halts its nuclear localization. Thus, the cell membrane-embedded ErbB-2, through endocytosis using the endocytic vesicle as a vehicle, importin beta 1 as a driver and Nup358 as a traffic light, migrates from the cell surface to the nucleus. This novel mechanism explains how a receptor tyrosine kinase on the cell surface can be translocated into the nucleus. This pathway may serve as a general mechanism to allow direct communication between cell surface receptors and the nucleus, and our findings thus open a new era in understanding direct trafficking between the cell membrane and nucleus.