来自华东师范大学的研究人员在新研究中证实，Akt可以发生SUMO化修饰，其调控了细胞增殖和肿瘤形成。这一研究发现发表在7月24日的《癌症研究》（Cancer Research）杂志上。
华东师范大学生命医学研究所的王平（Ping Wang）教授是这篇论文的通讯作者。其主要研究方向包括细胞信号传导，炎性细胞迁移的分子机制，以及肿瘤及干细胞中关键蛋白的调控机制。
丝氨酸／苏氨酸蛋白激酶B (protein kinase B, PKB/Akt)是一种癌基因，它通过磷酸化其下游分子，参与或介导细胞周期调节、细胞生长、细胞凋亡、细胞增殖等多种生物学活性，从而参与肿瘤的发生、发展。
Akt作为磷脂酰肌醇-3-激酶(phosphoinositide-3-kinase,PI3K)信号转导通路下游的信息、分子,已在许多常见肿瘤的研究中发现其过量表达。因此，Akt可能为肿瘤的治疗提供新的靶点，Akt的研究也已成为目前热点。Akt共有3种亚型即Aktl，Akt2和Akt3。其中Aktl的研究更为常见。过去的研究证实，翻译后修饰如磷酸化、泛素化、乙酰化都可以激活Akt1，在细胞生物学功能中发挥着非常重要的作用。
在这篇新文章中，研究人员报告称证实SUMO化修饰是一种新型的Akt激活机制。通过系统地分析赖氨酸残基在Akt激活中的作用，他们揭示定位在SUMO化修饰共有基序（consensus motif）中的K276对Akt激活至关重要。SUMO化修饰可以改变异位表达及内源的Akt1。研究人员证实用RNAi介导UBC9沉默可以抑制Akt的SUMO化修饰，SUMO E3连接酶PIAS1可以促进这一效应，而SUMO特异性的蛋白酶SENP1则能够逆转这一效应。
尽管Akt上有多个位点可以发生SUMO化修饰，研究人员证实K276是一个较重要的SUMO接受位点。K276R或E278A突变可以减少Akt的SUMO化修饰，但对其泛素化影响很小。并且这些突变还可以完全破坏Akt激酶的活性。
与上述结果相一致的是，研究人员发现表达PIAS1和SUMO1可以提高Akt1的活性，而表达SENP1则可降低Akt1的活性。有趣的是，在各种癌症中发生的Akt1 E17K突变相比于野生型Akt能够更有效地发生SUMO化修饰。并且，SUMO化修饰丧失可显著抑制Akt1 E17K介导的细胞增殖、细胞迁移和肿瘤形成。
这些研究结果确立了Akt SUMO化修饰是Akt功能激活的一种新调控机制。（生物谷 Bioon.com）
生物谷推荐的英文摘要
Cancer Research doi: 10.1158/0008-5472.CAN-13-0538
Akt SUMOylation regulates cell proliferation and tumorigenesis
Rong Li1, Jie Wei1, Cong Jiang1, Dongmei Liu1, Lu Deng1, Kai Zhang1, and Ping Wang1
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. RNAi-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 supporting of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, while expression of SENP1 reduced Akt1 activity. Interestingly, the cancer-derived mutant E17K in Akt1 which 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.
