Nakahata Shingo, Ichikawa Tomonaga, Maneesaay Phudit, Saito Yusuke, Nagai Kentaro, Tamura Tomohiro, Manachai Nawin, Yamakawa Norio, Hamasaki Makoto, Kitabayashi Issay, Arai Yasuhito, Kanai Yae, Taki Tomohiko, Abe Takaya, Kiyonari Hiroshi, Shimoda Kazuya, Ohshima Koichi, Horii Akira, Shima Hiroshi, Taniwaki Masafumi, Yamaguchi Ryoji, Morishita Kazuhiro
1] Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan [2].
Department of Veterinary Pathology, University of Miyazaki, Nishi 1-1, Gakuen Kibana Dai, Miyazaki 889-2192, Japan.
Nat Commun. 2014 Feb 26;5:3393. doi: 10.1038/ncomms4393.
Constitutive phosphatidylinositol 3-kinase (PI3K)-AKT activation has a causal role in adult T-cell leukaemia-lymphoma (ATLL) and other cancers. ATLL cells do not harbour genetic alterations in PTEN and PI3KCA but express high levels of PTEN that is highly phosphorylated at its C-terminal tail. Here we report a mechanism for the N-myc downstream-regulated gene 2 (NDRG2)-dependent regulation of PTEN phosphatase activity via the dephosphorylation of PTEN at the Ser380, Thr382 and Thr383 cluster within the C-terminal tail. We show that NDRG2 is a PTEN-binding protein that recruits protein phosphatase 2A (PP2A) to PTEN. The expression of NDRG2 is frequently downregulated in ATLL, resulting in enhanced phosphorylation of PTEN at the Ser380/Thr382/Thr383 cluster and enhanced activation of the PI3K-AKT pathway. Given the high incidence of T-cell lymphoma and other cancers in NDRG2-deficient mice, PI3K-AKT activation via enhanced PTEN phosphorylation may be critical for the development of cancer.
组成型磷脂酰肌醇3激酶（PI3K）-AKT激活在成人T细胞白血病淋巴瘤（ATLL）和其他癌症中起因果作用。ATLL细胞在PTEN和PI3KCA中没有基因改变，但表达高水平的PTEN，其在C末端尾巴高度磷酸化。在这里，我们报告了一种机制，即N-myc下游调节基因2（NDRG2）通过在C末端尾巴的Ser380、Thr382和Thr383簇处使PTEN去磷酸化来依赖性调节PTEN磷酸酶活性。我们表明NDRG2是一种PTEN结合蛋白，可将蛋白磷酸酶2A（PP2A）募集到PTEN。NDRG2的表达在ATLL中经常下调，导致PTEN在Ser380/Thr382/Thr383簇处的磷酸化增强以及PI3K-AKT途径的激活增强。鉴于NDRG2缺陷小鼠中T细胞淋巴瘤和其他癌症的高发病率，通过增强PTEN磷酸化激活PI3K-AKT可能对癌症的发展至关重要。
