Cancer Research:華東師範大學王平等發現Akt可調控細胞增殖和腫瘤...

來自華東師範大學的研究人員在新研究中證實，Akt可以發生SUMO化修飾，其調控了細胞增殖和腫瘤形成。這一研究發現發表在7月24日的《癌症研究》（Cancer Research）雜誌上。

華東師範大學生命醫學研究所的王平（Ping Wang）教授是這篇論文的通訊作者。其主要研究方向包括細胞信號傳導，炎性細胞遷移的分子機制，以及腫瘤及幹細胞中關鍵蛋白的調控機制。

絲氨酸／蘇氨酸蛋白激酶B (protein kinase B, PKB/Akt)是一種癌基因，它通過磷酸化其下遊分子，參與或介導細胞周期調節、細胞生長、細胞凋亡、細胞增殖等多種生物學活性，從而參與腫瘤的發生、發展。

Akt作為磷脂醯肌醇-3-激酶(phosphoinositide-3-kinase,PI3K)信號轉導通路下遊的信息、分子,已在許多常見腫瘤的研究中發現其過量表達。因此，Akt可能為腫瘤的治療提供新的靶點，Akt的研究也已成為目前熱點。Akt共有3種亞型即Aktl，Akt2和Akt3。其中Aktl的研究更為常見。過去的研究證實，翻譯後修飾如磷酸化、泛素化、乙醯化都可以激活Akt1，在細胞生物學功能中發揮著非常重要的作用。

在這篇新文章中，研究人員報告稱證實SUMO化修飾是一種新型的Akt激活機制。通過系統地分析賴氨酸殘基在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Akt激活至關重要。SUMO化修飾可以改變異位表達及內源的Akt1。研究人員證實用RNAi介導UBC9沉默可以抑制Akt的SUMO化修飾，SUMO E3連接酶PIAS1可以促進這一效應，而SUMO特異性的蛋白酶SENP1則能夠逆轉這一效應。

儘管Akt上有多個位點可以發生SUMO化修飾，研究人員證實K276是一個較重要的SUMO接受位點。K276R或E278A突變可以減少Akt的SUMO化修飾，但對其泛素化影響很小。並且這些突變還可以完全破壞Akt激酶的活性。

與上述結果相一致的是，研究人員發現表達PIAS1和SUMO1可以提高Akt1的活性，而表達SENP1則可降低Akt1的活性。有趣的是，在各種癌症中發生的Akt1 E17K突變相比於野生型Akt能夠更有效地發生SUMO化修飾。並且，SUMO化修飾喪失可顯著抑制Akt1 E17K介導的細胞增殖、細胞遷移和腫瘤形成。

這些研究結果確立了Akt SUMO化修飾是Akt功能激活的一種新調控機制。（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.