Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62
Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62
复制标题
MUC1-C 癌蛋白的核输入由核孔蛋白 Nup62 介导
DOI：
10.1074/jbc.m703222200
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发表时间：
2007-07-06
影响因子：
4.8
通讯作者：
Kufe, Donald
中科院分区：
文献类型：
--
作者：
Leng, Yumei;Cao, Cheng;Kufe, Donald
MUC1异源二聚体跨膜蛋白在大多数人类肿瘤中异常过表达。MUC1C-末端亚单位(MUC1C)缺乏经典的核定位信号，通过未知的机制定位于核。目前的结果表明，MUC1-C与Importinβ结合，而不与Importinα结合。结果还表明，与Importin beta一样，MUC1-C也与Nup62(核孔素p62)结合。MUC1-C直接结合到Nup62的中心结构域，间接结合到Nup62的C末端α螺旋螺旋线圈结构域。我们证明了MUC1-C形成低聚物，并且寡聚是与Nup62结合所必需的。MUC1-C胞质结构域包含一个CQC基序，当突变为AQA时，该基序会取消寡聚作用并与Nup62结合。具有CQC->；AQA突变的MUC1的稳定表达与靶向细胞膜和胞浆以及核定位的减弱有关。结果进一步表明，MUC1(CQC-AQA)的表达减弱了MUC1诱导的(I)转录共激活，(Ii)锚定非依赖性生长和(Iii)致瘤性。这些发现表明，MUC1-C癌蛋白是通过涉及Nup62的途径输入到细胞核的。
The MUC1 heterodimeric transmembrane protein is aberrantly overexpressed by most human carcinomas. The MUC1 C-terminal subunit (MUC1-C) is devoid of a classical nuclear localization signal and is targeted to the nucleus by an unknown mechanism. The present results demonstrate that MUC1-C associates with importin beta and not importin alpha. The results also show that, like importin beta, MUC1-C binds to Nup62 ( nucleoporin p62). MUC1-C binds directly to the Nup62 central domain and indirectly to the Nup62 C-terminal alpha-helical coiled-coil domain. We demonstrate that MUC1-C forms oligomers and that oligomerization is necessary for binding to Nup62. The MUC1-C cytoplasmic domain contains a CQC motif that when mutated to AQA abrogates oligomerization and binding to Nup62. Stable expression of MUC1 with the CQC -> AQA mutations was associated with targeting to the cell membrane and cytosol and attenuation of nuclear localization. The results further show that expression of MUC1(CQC-AQA) attenuates MUC1-induced (i) transcriptional coactivation, (ii) anchorage-independent growth, and (iii) tumorigenicity. These findings indicate that the MUC1-C oncoprotein is imported to the nucleus by a pathway involving Nup62.