Ubiquitination of RhoA by Smurf1 promotes neurite outgrowth
Ubiquitination of RhoA by Smurf1 promotes neurite outgrowth
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DOI：
10.1016/j.febslet.2004.12.074
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发表时间：
2005-02-14
期刊：
影响因子：
3.5
通讯作者：
Liu, MY
中科院分区：
文献类型：
--
作者：
Bryan, B;Cai, Y;Liu, MY
小gtpase的rho家族包括神经突生长、轴突寻路和树突树突形成的重要调节因子。先前的研究表明，在非神经元细胞类型中，E3泛素连接酶Smurf1通过pkceta依赖性募集到细胞突起位点，以及随后的RhoA泛素化和蛋白酶体降解来调节细胞极性和突起活性。在这项研究中，我们发现Smurf1促进了Neuro2a神经母细胞瘤细胞的神经突生长。我们证明RhoA是泛素化的，并且Smurf1和RhoA在体内物理相互作用。有趣的是，在二丁基环AMP过程中，Smurf1在Neuro2a细胞中的过表达会显著降低RhoA蛋白水平，但维甲酸不会诱导神经突生长。这种依赖Smurf1的RhoA蛋白水平降低被通用蛋白酶体抑制剂MG132所消除，这表明RhoA是通过Smurf1泛素化和降解的目标。总之，我们的数据表明，通过特定的引导信号对Rho gtpase不同亚群的局部调控导致细胞内RhoA活性的不对称，从而调节神经突起的生长和引导。(C) 2005年欧洲生化学会联合会。Elsevier B.V.版权所有。
The Rho-family of small GTPases consists of essential regulators of neurite outgrowth, axonal pathfinding, and dendritic arborization. Previous work has demonstrated in non-neuronal cell types that Smurf1, an E3 ubiquitin ligase, regulates cell polarity and protrusive activity via PKCzeta-dependent recruitment to cellular protrusion sites, and subsequent ubiquitination and proteasomal degradation of RhoA. In this study, we show that Smurf1 enhances neurite outgrowth in Neuro2a neuroblastoma cells. We demonstrate that RhoA is ubiquitinated, and that Smurf1 and RhoA physically interact in vivo. Interestingly, Smurf1 overexpression in Neuro2a cells dramatically reduces RhoA protein levels during dibutyric cyclic AMP, but not retinoic acid induced neurite outgrowth. This Smurf1-dependent reduction in RhoA protein levels was abrogated using the general proteasome inhibitor MG132, suggesting that RhoA is targeted for ubiquitination and degradation via Smurf1. Together, our data suggest that localized regulation of different subsets of Rho GTPases by specific guidance signals results in an intracellular asymmetry of RhoA activity, which could regulate neurite outgrowth and guidance. (C) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.