SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane
SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane
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PTEN 的 SUMO1 修饰通过控制其与质膜的关联来调节肿瘤发生
DOI：
10.1038/ncomms1919
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发表时间：
2012-06-01
影响因子：
16.6
通讯作者：
Yu, Jianxiu
中科院分区：
文献类型：
--
作者：
Huang, Jian;Yan, Jie;Yu, Jianxiu
需要肿瘤抑制剂磷酸酶和张力蛋白同源物（PTEN）的膜缔合以通过磷脂酰肌醇-3，4，5-三磷酸（PIP 3）的去磷酸化来对抗磷脂酰肌醇-3-激酶/AKT途径。胞浆中的PTEN如何与位于质膜内表面的其主要底物PIP 3相互作用仍不清楚。我们发现SUMO 1在PTEN C2结构域的K266和K254位点共价修饰了PTEN。位于CBR 3环K266的SUMO 1修饰在PTEN膜结合中起核心作用，主要通过静电相互作用促进PTEN与质膜的协同结合。这导致磷脂酰肌醇-3激酶/AKT通路的下调，从而抑制锚定非依赖性细胞增殖和体内肿瘤生长。我们的数据表明，SUMO 1修饰是必需的PTEN肿瘤抑制功能，通过控制PTEN膜协会和调节磷脂酰肌醇-3激酶/AKT途径的分子机制。
The membrane association of the tumour suppressor phosphatase and tensin homologue (PTEN) is required to oppose the phosphatidylinositol-3-kinase/AKT pathway by dephosphorylation of phosphatidylinositol-3,4,5-triphosphate (PIP3). How cytosolic PTEN interacts with its main substrate, PIP3, localized at the inner face of plasma membrane remains unclear. Here we show that PTEN is covalently modified by SUMO1 at both K266and K254sites in the C2 domain of PTEN. SUMO1 modification at K266located in the CBR3 loop, which has a central role in PTEN membrane association, mainly facilitates cooperative binding of PTEN to the plasma membrane by electrostatic interactions. This results in the downregulation of the phosphatidylinositol-3 kinase/AKT pathway and consequently, suppression of anchorage-independent cell proliferation and tumour growthin vivo. Our data demonstrate a molecular mechanism whereby SUMO1 modification is required for PTEN tumour suppressor function by controlling PTEN membrane association and regulation of the phosphatidylinositol-3 kinase/AKT pathway.