Altered glycosylation of MUC1 influences its association with CIN85: the role of this novel complex in cancer cell invasion and migration.
Altered glycosylation of MUC1 influences its association with CIN85: the role of this novel complex in cancer cell invasion and migration.
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DOI：
10.18632/oncotarget.1265
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Finn OJ
中科院分区：
文献类型：
--
作者：
Cascio S;Farkas AM;Hughey RP;Finn OJ
MUC 1是一种跨膜糖蛋白，在人类腺癌中异常表达。MUC 1的胞外结构域包含一个可变数目的串联重复序列（VNTR）区域，该区域在正常上皮细胞中广泛糖基化，而在肿瘤细胞中糖基化不足。MUC 1翻译后修饰的这种变化导致其正常功能的变化，我们假设包括其与其他分子的相互作用。我们鉴定了CIN 85，一种参与多个细胞过程的衔接蛋白，包括信号转导、细胞骨架重塑和癌细胞侵袭，作为肿瘤细胞中与MUC 1相关的几种蛋白之一。CIN 85与MUC 1的胞质尾区和细胞外VNTR结合。共免疫沉淀和共聚焦免疫荧光证实，MUC 1和CIN 85共定位主要在质膜，但复合物也可以在细胞溶质和细胞骨架上发现。MUC 1和CIN 85在乳腺癌的早期和晚期临床阶段都过表达，并共同定位于与细胞侵袭有关的侵袭伪足样结构上。siRNA介导的CIN 85和/或MUC 1的沉默揭示了MUC 1在体外增强CIN 85依赖性乳腺癌细胞的迁移和侵袭。然而，MUC 1的异位表达增强了由CIN 85诱导的运动。当在B16黑色素瘤的肿瘤转移模型中进行体内测试时，注射CIN 85耗尽的黑色素瘤细胞的小鼠表现出很少或没有肺转移，并且与体外结果类似，MUC 1的过表达恢复了shCIN 85减少的转移过程。我们的研究结果表明，这种新发现的CIN 85/MUC 1复合物与侵袭足相关分子相关，促进了乳腺癌的侵袭和转移潜力。
MUC1 is a transmembrane glycoprotein abnormally expressed in human adenocarcinomas. The extracellular domain of MUC1 contains a variable number of tandem repeats (VNTR) region that is extensively O-glycosylated in normal epithelia and underglycosylated in tumor cells. This change in posttranslational modification of MUC1 leads to changes in its normal functions including, we hypothesized, its interaction with other molecules. We identified CIN85, an adaptor protein involved in multiple cellular processes including signal transduction, cytoskeletal remodeling and cancer cell invasion, as one of several proteins that associate with MUC1 in tumor cells. CIN85 associates with both the cytosolic tail and the extracellular VNTR of MUC1. Co-immunoprecipitation and confocal immunofluorescence confirmed that MUC1 and CIN85 co-localize primarily at the plasma membrane but the complex can be found also in the cytosol and on the cytoskeleton. MUC1 and CIN85 are both over-expressed in early as well as advanced clinical stages of breast cancer and co-localize on invadopodia-like structures implicated in cell invasion. siRNA-mediated silencing of CIN85 and/or MUC1 revealed that MUC1 enhances CIN85-dependent breast cancer cell migration and invasion in vitro. However, ectopic expression of MUC1 enhances the motility induced by CIN85. When tested in vivo in a tumor metastasis model of B16 melanoma, mice injected with CIN85-depleted melanoma cells exhibited few or no lung metastasis and, similarly to the in vitro results, overexpression of MUC1 recovered the shCIN85-reduced metastatic process. Our findings implicate this newly identified CIN85/MUC1 complex associated with invadopodia-related molecules in promoting the invasive and metastatic potential of breast cancer.
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DOI：
10.1083/jcb.200706108
发表时间：
2008-03-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnson RI;Seppa MJ;Cagan RL
通讯作者：
Cagan RL
影响因子：
4.8
作者：
Kowanetz, K;Szymkiewicz, I;Dikic, I
通讯作者：
Dikic, I
影响因子：
--
作者：
Pegoraro S;Ros G;Piazza S;Sommaggio R;Ciani Y;Rosato A;Sgarra R;Del Sal G;Manfioletti G
通讯作者：
Manfioletti G
影响因子：
4
作者：
Kamata, M;Denda-Nagai, K;Irimura, T
通讯作者：
Irimura, T
DOI：
10.1080/07391102.1995.10508837
发表时间：
1995-10-01
影响因子：
4.4
作者：
FONTENOT, JD;MARIAPPAN, SVS;GUPTA, G
通讯作者：
GUPTA, G