來(lái)自華東師范大學(xué)的研究人員在新研究中證實(shí),，Akt可以發(fā)生SUMO化修飾，其調(diào)控了細(xì)胞增殖和腫瘤形成,。這一研究發(fā)現(xiàn)發(fā)表在7月24日的《癌癥研究》（Cancer Research）雜志上,。
華東師范大學(xué)生命醫(yī)學(xué)研究所的王平（Ping Wang）教授是這篇論文的通訊作者。其主要研究方向包括細(xì)胞信號(hào)傳導(dǎo),，炎性細(xì)胞遷移的分子機(jī)制,，以及腫瘤及干細(xì)胞中關(guān)鍵蛋白的調(diào)控機(jī)制。
絲氨酸／蘇氨酸蛋白激酶B (protein kinase B, PKB/Akt)是一種癌基因,，它通過(guò)磷酸化其下游分子,，參與或介導(dǎo)細(xì)胞周期調(diào)節(jié)、細(xì)胞生長(zhǎng),、細(xì)胞凋亡,、細(xì)胞增殖等多種生物學(xué)活性，從而參與腫瘤的發(fā)生,、發(fā)展,。
Akt作為磷脂酰肌醇-3-激酶(phosphoinositide-3-kinase,PI3K)信號(hào)轉(zhuǎn)導(dǎo)通路下游的信息,、分子,已在許多常見(jiàn)腫瘤的研究中發(fā)現(xiàn)其過(guò)量表達(dá)。因此,，Akt可能為腫瘤的治療提供新的靶點(diǎn),，Akt的研究也已成為目前熱點(diǎn)。Akt共有3種亞型即Aktl,，Akt2和Akt3,。其中Aktl的研究更為常見(jiàn)。過(guò)去的研究證實(shí),，翻譯后修飾如磷酸化,、泛素化、乙?；伎梢约せ預(yù)kt1,，在細(xì)胞生物學(xué)功能中發(fā)揮著非常重要的作用。
在這篇新文章中,，研究人員報(bào)告稱(chēng)證實(shí)SUMO化修飾是一種新型的Akt激活機(jī)制,。通過(guò)系統(tǒng)地分析賴(lài)氨酸殘基在Akt激活中的作用，他們揭示定位在SUMO化修飾共有基序（consensus motif）中的K276對(duì)Akt激活至關(guān)重要,。SUMO化修飾可以改變異位表達(dá)及內(nèi)源的Akt1,。研究人員證實(shí)用RNAi介導(dǎo)UBC9沉默可以抑制Akt的SUMO化修飾，SUMO E3連接酶PIAS1可以促進(jìn)這一效應(yīng),，而SUMO特異性的蛋白酶SENP1則能夠逆轉(zhuǎn)這一效應(yīng),。
盡管Akt上有多個(gè)位點(diǎn)可以發(fā)生SUMO化修飾，研究人員證實(shí)K276是一個(gè)較重要的SUMO接受位點(diǎn),。K276R或E278A突變可以減少Akt的SUMO化修飾,，但對(duì)其泛素化影響很小。并且這些突變還可以完全破壞Akt激酶的活性,。
與上述結(jié)果相一致的是,，研究人員發(fā)現(xiàn)表達(dá)PIAS1和SUMO1可以提高Akt1的活性,，而表達(dá)SENP1則可降低Akt1的活性,。有趣的是，在各種癌癥中發(fā)生的Akt1 E17K突變相比于野生型Akt能夠更有效地發(fā)生SUMO化修飾,。并且,，SUMO化修飾喪失可顯著抑制Akt1 E17K介導(dǎo)的細(xì)胞增殖、細(xì)胞遷移和腫瘤形成,。
這些研究結(jié)果確立了Akt SUMO化修飾是Akt功能激活的一種新調(diào)控機(jī)制,。（生物谷 Bioon.com）
生物谷推薦的英文摘要
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.
