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首页> 外文期刊>The FEBS journal >Activated Rac1, but not the tumorigenic variant Rac1b, is ubiquitinated on Lys 147 through a JNK-regulated process
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Activated Rac1, but not the tumorigenic variant Rac1b, is ubiquitinated on Lys 147 through a JNK-regulated process

机译：通过JNK调控的过程，活化的Rac1，而不是致癌变体Rac1b，在Lys 147上泛素化

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摘要

Ubiquitination and proteasomal degradation have recently emerged as an additional level of regulation of activated forms of Rho GTPases. To characterize this novel regulatory pathway and to gain insight into its biological significance, we studied the ubiquitination of two constitutively activated forms of Rac1, i.e. the mutationally activated Rac1L61, and the tumorigenic splice variant Rac1b, which is defective for several downstream signaling pathways, including JNK activation. Whereas Rac1L61 undergoes polyubiquitination and subsequent proteasomal degradation in HEK293 cells, Rac1b is poorly ubiquitinated and appears to be much more resistant to proteasomal degradation than Rac1L61. Mutational analysis of all lysine residues in Rac1 revealed that the major target site for Rac1 ubiquitination is Lys147, a solvent-accessible residue that has a similar conformation in Rac1b. Like Rac1L61, Rac1b was found to be largely associated with plasma membrane, a known prerequisite for Rac1 ubiquitination. Interestingly, Rac1b ubiquitination could be stimulated by coexpression of Rac1L61, suggesting positive regulation of Rac1 ubiquitination by Rac1 downstream signaling. Indeed, ubiquitination of Rac1L61 is critically dependent on JNK activation. In conclusion: (a) Rac1b appears to be more stable than Rac1L61 with regard to the ubiquitin-proteasome system, and this may be of importance for the expression and tumorigenic capacity of Rac1b; and (b) ubiquitination of activated Rac1 occurs through a JNK-activated process, which may explain the defective ubiquitination of Rac1b. The JNK-dependent activation of Rac1 ubiquitination would create a regulatory loop allowing the cell to counteract excessive activation of Rac1 GTPase.
机译：泛素化和蛋白酶体降解最近已作为Rho GTPases活化形式的额外调节水平出现。为了表征这种新颖的调节途径并深入了解其生物学意义，我们研究了Rac1的两种组成型激活形式的泛素化，即突变激活的Rac1L61和致瘤性剪接变体Rac1b的存在，该变体对一些下游信号通路均存在缺陷JNK激活。 Rac1L61在HEK293细胞中经历了泛素化和随后的蛋白酶体降解，而Rac1b的泛素化程度较差，并且似乎比Rac1L61对蛋白酶体降解的抵抗力强得多。对Rac1中所有赖氨酸残基的突变分析显示，Rac1泛素化的主要目标位点是Lys147，这是一种溶剂可接近的残基，在Rac1b中具有相似的构象。像Rac1L61一样，发现Rac1b与质膜很大程度上相关，这是Rac1泛素化的已知先决条件。有趣的是，Rac1L61的共表达可能会刺激Rac1b泛素化，表明Rac1下游信号转导对Rac1泛素化具有积极的调节作用。确实，Rac1L61的泛素化关键取决于JNK激活。结论：（a）就泛素-蛋白酶体系统而言，Rac1b似乎比Rac1L61更稳定，这可能对Rac1b的表达和致瘤能力具有重要意义; （b）活化的Rac1的泛素化是通过JNK激活的过程发生的，这可以解释Rac1b泛素化的缺陷。 Rac1泛素化的JNK依赖激活将创建一个调节环，使细胞能够抵消Rac1 GTPase的过度激活。

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