Regulation of CNKSR2 protein stability by the HECT E3 ubiquitin ligase Smurf2, and its role in breast cancer progression.
Regulation of CNKSR2 protein stability by the HECT E3 ubiquitin ligase Smurf2, and its role in breast cancer progression.
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DOI：
10.1186/s12885-018-4188-x
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发表时间：
2018-03-13
期刊：
影响因子：
3.8
通讯作者：
Nair AS
中科院分区：
文献类型：
--
作者：
David D;Surendran A;Thulaseedharan JV;Nair AS
Smurf 2 E3泛素连接酶与不同的细胞蛋白质底物物理关联并调节其稳定性。多功能支架蛋白连接增强子激酶抑制因子2（CNKSR 2）通过多种受体酪氨酸激酶途径在调节细胞增殖和分化中起关键作用。本研究的目的是研究Smurf 2和CNKSR 2之间的相互作用是否在乳腺癌CNKSR 2表达的转录后调控中具有任何重要作用。研究方法：在这里，我们证明了一种新的相互作用CNKSR 2与Smurf 2的免疫共沉淀，间接免疫荧光研究，表面等离子体共振（SPR）分析，它可以泛素化，但稳定CNKSR 2保护它免受蛋白酶体介导的降解。CNKSR 2蛋白水平在Smurf 2的强制过表达后显著增加，表明Smurf 2在调节CNKSR 2稳定性中的作用。相反，Smurf 2敲低通过促进增强的多聚泛素化和蛋白酶体降解导致CNKSR 2蛋白水平表达的显著降低，并降低MDA-MB-231乳腺癌细胞系的增殖和克隆形成存活。来自84名患有不同阶段乳腺癌的患者的组织微阵列数据，包括（按照恶性潜能增加的顺序）正常、普通增生、纤维囊性变化、纤维腺瘤、原位癌和浸润性导管癌，显示Smurf 2和CNKSR 2表达之间的统计学显著相关性，这也与组织样本的ER、PR和HER 2状态良好相关。当ER和PR表达低，HER 2表达高时，观察到Smurf 2和CNKSR 2的相对高表达。一致地，Smurf 2和CNKSR 2在MCF 10乳腺进展模型细胞系中显示整合表达。总之，我们的研究结果表明，Smurf 2是一种新的CNKSR 2的正调节因子，并表明Smurf 2-CNKSR 2相互作用可能作为一种常见的策略，通过调节CNKSR 2蛋白的稳定性来控制人乳腺癌细胞的增殖。本文的在线版本（10.1186/s12885-018-4188-x）包含补充材料，可供授权用户使用。
Smurf2 E3 ubiquitin ligase physically associates with and regulate the stability of distinct cellular protein substrates. The multi-functional scaffold protein Connector enhancer of kinase suppressor of ras 2 (CNKSR2) plays a key role in regulating cell proliferation, and differentiation through multiple receptor tyrosine kinase pathways. The aim of this study was to investigate whether the interaction between Smurf2 and CNKSR2 has any significant role in the post transcriptional regulation of CNKSR2 expression in breast cancer. Methods: Here we demonstrate a novel interaction of CNKSR2 with Smurf2 by co-immunoprecipitation, indirect immunofluorescence studies, and surface plasmon resonance (SPR) analysis, which can ubiquitinate, but stabilize CNKSR2 by protecting it from proteasome mediated degradation. CNKSR2 protein levels were significantly increased upon forced overexpression of Smurf2, indicating the role of Smurf2 in regulating the stability of CNKSR2. Conversely, Smurf2 knockdown resulted in a marked decrease in the protein level expression of CNKSR2 by facilitating enhanced polyubiquitination and proteasomal degradation and reduced the proliferation and clonogenic survival of MDA-MB-231 breast cancer cell lines. Tissue microarray data from 84 patients with various stages of mammary carcinoma, including (in order of increasing malignant potential) normal, usual hyperplasia, fibrocystic changes, fibroadenoma, carcinoma-in-situ, and invasive ductal carcinoma showed a statistically significant association between Smurf2 and CNKSR2 expression, which is also well correlated with the ER, PR, and HER2 status of the tissue samples. A comparatively high expression of Smurf2 and CNKSR2 was observed when the expression of ER and PR was low, and HER2 was high. Consistently, both Smurf2 and CNKSR2 showed an integrated expression in MCF10 breast progression model cell lines. Altogether, our findings reveal that Smurf2 is a novel positive regulator of CNKSR2 and suggest that Smurf2-CNKSR2 interaction may serve as a common strategy to control proliferation of human breast cancer cells by modulating CNKSR2 protein stability. The online version of this article (10.1186/s12885-018-4188-x) contains supplementary material, which is available to authorized users.
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影响因子：
82.9
作者：
Kononen, J;Bubendorf, L;Kallioniemi, OP
通讯作者：
Kallioniemi, OP
HECT E3连接酶Smurf2是MAD2依赖性纺锤体组件检查点所需的。
影响因子：
7.8
作者：
Osmundson, Evan C.;Ray, Dipankar;Moore, Finola E.;Gao, Qingshen;Thomsen, Gerald H.;Kiyokawa, Hiroaki
通讯作者：
Kiyokawa, Hiroaki
影响因子：
4.8
作者：
Ray, Dipankar;Ahsan, Aarif;Nyati, Mukesh K.
通讯作者：
Nyati, Mukesh K.
影响因子：
64.8
作者：
Zhu, HT;Kavsak, P;Thomsen, GH
通讯作者：
Thomsen, GH
影响因子：
16
作者：
Kavsak, P;Rasmussen, RK;Wrana, JL
通讯作者：
Wrana, JL