Nuclear localization of PTEN by a ran-dependent mechanism enhances apoptosis:: Involvement of an N-terminal nuclear localization domain and multiple nuclear exclusion motifs
Nuclear localization of PTEN by a ran-dependent mechanism enhances apoptosis:: Involvement of an N-terminal nuclear localization domain and multiple nuclear exclusion motifs
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DOI：
10.1091/mbc.e06-05-0380
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发表时间：
2006-09-01
影响因子：
3.3
通讯作者：
Pulido, Rafael
中科院分区：
文献类型：
--
作者：
Gil, Anabel;Andres-Pons, Amparo;Pulido, Rafael
肿瘤抑制因子PTEN蛋白靶向不同的亚细胞区室是PTEN功能的主要调控机制，通过控制其对底物和效应蛋白的获取。在这里，我们研究了PTEN核/细胞质分布的分子基础和功能后果。PTEN在受到凋亡刺激的细胞核中积累。PTEN的核积累通过靶向不同PTEN结构域的基序的突变而增强，并且依赖于n端核定位结构域。显性阴性Ran GTPase蛋白的共表达阻断了PTEN在细胞核中的积累，这也受到输入蛋白a的共表达的影响。PTEN的脂质和蛋白磷酸酶活性差异调节PTEN核积累。此外，具有催化活性的核PTEN增强了细胞凋亡反应。我们的研究结果表明，多个核排斥基序和一个核定位结构域通过一种ran依赖机制控制PTEN的核定位，并提示PTEN在细胞核中具有促凋亡作用。
The targeting of the tumor suppressor PTEN protein to distinct subcellular compartments is a major regulatory mechanism of PTEN function, by controlling its access to substrates and effector proteins. Here, we investigated the molecular basis and functional consequences of PTEN nuclear/cytoplasmic distribution. PTEN accumulated in the nucleus of cells treated with apoptotic stimuli. Nuclear accumulation of PTEN was enhanced by mutations targeting motifs in distinct PTEN domains, and it was dependent on an N-terminal nuclear localization domain. Coexpression of a dominant negative Ran GTPase protein blocked PTEN accumulation in the nucleus, which was also affected by coexpression of importin a proteins. The lipid- and protein-phosphatase activity of PTEN differentially modulated PTEN nuclear accumulation. Furthermore, catalytically active nuclear PTEN enhanced cell apoptotic responses. Our findings indicate that multiple nuclear exclusion motifs and a nuclear localization domain control PTEN nuclear localization by a Ran-dependent mechanism and suggest a proapoptotic role for PTEN in the cell nucleus.