A novel role of Rac1 GTPase in JCV T-antigen-mediated β-catenin stabilization
A novel role of Rac1 GTPase in JCV T-antigen-mediated β-catenin stabilization
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DOI：
10.1038/sj.onc.1210576
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发表时间：
2007-12-06
期刊：
影响因子：
8
通讯作者：
Khalili, K.
中科院分区：
文献类型：
--
作者：
Bhattacharyya, R.;Noch, E. K.;Khalili, K.
WNT信号遵循规范和非规范途径，在细胞内稳态和发育过程中调节各种过程。人类嗜神经性JC病毒的大T抗原(T-Ag)通过与典型的Wnt途径中最重要的成分之一β-连环蛋白相互作用来调节Wnt信号通路。在这里，我们已经确定了一种替代的非典型途径，允许T-Ag通过抑制其泛素依赖的蛋白酶体降解来招募rac1来稳定β-连环蛋白。我们证明，其显性负突变体racN17对rac1的抑制可以消除T-Ag介导的b-catenin的稳定，但对b-catenin的转录活性没有影响。免疫细胞化学结果显示，与T-Ag一起，β-连环素池出现在细胞表面，特别是在具有活性的rac1所在的膜褶皱处。有趣的是，T-Ag和β-连环蛋白之间的协同作用导致了rac1的激活，进而刺激了它与β-连环蛋白的联系。这些观察揭示了由T-Ag启动的β-连环蛋白与rac1之间的相互作用，并导致了β-连环蛋白的稳定及其在细胞膜褶皱中的存在。
Wnt signaling follows canonical and non-canonical pathways to regulate a variety of processes during cellular homeostasis and development. The large T-antigen (T-Ag) of the human neurotropic JC virus, has been shown to modulate the Wnt-signaling pathway via interaction with beta-catenin, one of the most important components of the canonical Wnt pathway. Here, we have identified an alternative non-canonical pathway that allows T-Ag to recruit Rac1 for stabilizing beta-catenin by inhibiting its ubiquitin-dependent proteasomal degradation. We demonstrate that inhibition of Rac1 by its dominant negative mutant, RacN17, abrogates T-Ag-mediated stabilization of b-catenin yet exhibits no impact on the transcriptional activity of b-catenin. Results from immunocytochemistry revealed that together with T-Ag, a pool of beta-catenin appears at the cell surface, particularly at the membrane ruffles where active Rac1 is positioned. Interestingly, cooperativity between T-Ag and beta-catenin leads to activation of Rac1, which in turn, stimulates its association with beta-catenin. These observations unravel the interplay between beta-catenin and Rac1 that is initiated by T-Ag and results in stabilization of beta-catenin and its presence in cell membrane ruffles.