Akt SUMOylation Regulates Cell Proliferation and Tumorigenesis
Akt SUMOylation Regulates Cell Proliferation and Tumorigenesis
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Akt SUMOylation 调节细胞增殖和肿瘤发生
DOI：
10.1158/0008-5472.can-13-0538
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发表时间：
2013-09-15
期刊：
影响因子：
11.2
通讯作者：
Wang, Ping
中科院分区：
文献类型：
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作者：
Li, Rong;Wei, Jie;Wang, Ping
原癌基因Akt在细胞增殖和肿瘤发生中起重要作用。Akt的完全激活受磷酸化、泛素化和乙酰化的调节。在这里，我们报告，SUMO化Akt是一种新的机制，其激活。系统地分析了赖氨酸残基在Akt活化中的作用，揭示了位于SUMO化共有基序中的K276对Akt活化是必需的。异位或内源性Akt1可以通过SUMO化修饰。RNA干扰介导的UBC9沉默减少了Akt SUMO化，这是由SUMO E3连接酶PIAS 1促进的，并由SUMO特异性蛋白酶SENP 1逆转。虽然Akt上的多个位点可以被SUMO化，但K276被鉴定为主要的SUMO受体位点。K276R或E278A突变降低了Akt的SUMO化，但对其泛素化影响不大。引人注目的是，这些突变也完全消除了Akt激酶活性。为了支持这些结果，我们发现PIAS 1和SUMO 1的表达增加了Akt活性，而SENP 1的表达降低了Akt 1活性。有趣的是，发生在各种癌症中的Akt1中的癌症衍生突变体E17 K比野生型Akt更有效地SUMO化。此外，SUMO化缺失显著降低了Akt1 E17 K介导的细胞增殖、细胞迁移和肿瘤发生。总的来说，我们的研究结果表明Akt SUMO化为激活Akt功能提供了一种新的调节机制。(C)2013年AACR。
Proto-oncogene Akt plays essential roles in cell proliferation and tumorigenesis. Full activation of Akt is regulated by phosphorylation, ubiquitination, and acetylation. Here we report that SUMOylation of Akt is a novel mechanism for its activation. Systematically analyzing the role of lysine residues in Akt activation revealed that K276, which is located in a SUMOylation consensus motif, is essential for Akt activation. Ectopic or endogenous Akt1 could be modified by SUMOylation. RNA interference-mediated silencing of UBC9 reduced Akt SUMOylation, which was promoted by SUMO E3 ligase PIAS1 and reversed by the SUMO-specific protease SENP1. Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity. Interestingly, the cancer-derived mutant E17K in Akt1 that occurs in various cancers was more efficiently SUMOylated than wild-type Akt. Moreover, SUMOylation loss dramatically reduced Akt1 E17K-mediated cell proliferation, cell migration, and tumorigenesis. Collectively, our findings establish that Akt SUMOylation provides a novel regulatory mechanism for activating Akt function. (C) 2013 AACR.