Pathophysiological significance of N-myc downstream-regulated gene 2 in cancer development through protein phosphatase 2A phosphorylation regulation.
Pathophysiological significance of N-myc downstream-regulated gene 2 in cancer development through protein phosphatase 2A phosphorylation regulation.
复制标题
DOI：
10.1111/cas.14716
复制
发表时间：
2021-01
期刊：
影响因子：
5.7
通讯作者：
Ichikawa T
中科院分区：
文献类型：
--
作者：
Morishita K;Nakahata S;Ichikawa T
N-myc下游调节基因2（NDRG 2）是多种癌症的候选肿瘤抑制因子，包括成人T细胞白血病/淋巴瘤（ATLL）。NDRG 2作为一种应激反应蛋白，由多种应激相关信号通路诱导，并且NDRG 2负调节多种信号转导通路。虽然还没有发现NDRG 2单独发挥作用，但它与丝氨酸/苏氨酸蛋白磷酸酶2A（PP 2A）结合，产生一种参与调节各种靶蛋白的复合物。NDRG 2的主要功能是通过抑制应激诱导的信号转导来维持细胞稳态;然而，在癌症中，基因组缺失和/或启动子甲基化可能会抑制NDRG 2的表达，从而通过过度激活的信号转导途径增强肿瘤的发展。在Ndrg 2缺陷小鼠中会发生多种肿瘤，包括T细胞淋巴瘤、肝、肺和其他肿瘤，其特征与Pten缺陷小鼠相似。特别地，PTEN是NDRG 2/PP 2A复合物的靶分子，其通过使PTEN C末端区域中的残基去磷酸化来增强PTEN磷酸酶活性。在ATLL细胞中，NDRG 2表达的丧失导致PP 2A向PTEN的募集失败，导致PTEN磷酸酶失活和磷酸化，最终导致PI 3 K/AKT的激活。因此，NDRG 2作为PP 2A接头，调节重要信号分子的全局磷酸化。此外，长期应激诱导的甲基化导致NDRG 2表达下调与ATLL和其他癌症的发展直接相关。因此，NDRG 2可能对应激诱导的白血病和其他癌症的发展很重要，并已成为新型分子治疗的重要靶点。在肿瘤细胞中，NDRG 2表达的丧失诱导了PTEN C末端的组成性磷酸化，这使PTEN保持在无活性的闭合构象并导致组成性AKT活化。
N‐myc downstream‐regulated gene 2 (NDRG2) is a candidate tumor suppressor in various cancers, including adult T‐cell leukemia/lymphoma (ATLL). NDRG2, as a stress‐responsive protein, is induced by several stress‐related signaling pathways and NDRG2 negatively regulates various signal transduction pathways. Although it has not been found to function alone, NDRG2 binds serine/threonine protein phosphatase 2A (PP2A), generating a complex that is involved in the regulation of various target proteins. The main function of NDRG2 is to maintain cell homeostasis by suppressing stress‐induced signal transduction; however, in cancer, genomic deletions and/or promoter methylation may inhibit the expression of NDRG2, resulting in enhanced tumor development through overactivated signal transduction pathways. A wide variety of tumors develop in Ndrg2‐deficient mice, including T‐cell lymphoma, liver, lung and other tumors, the characteristics of which are similar to those in Pten‐deficient mice. In particular, PTEN is a target molecule of the NDRG2/PP2A complex, which enhances PTEN phosphatase activity by dephosphorylating residues in the PTEN C‐terminal region. In ATLL cells, loss of NDRG2 expression leads to the failed recruitment of PP2A to PTEN, resulting in the inactivation of PTEN phosphatase with phosphorylation, ultimately leading to the activation of PI3K/AKT. Thus, NDRG2, as a PP2A adaptor, regulates the global phosphorylation of important signaling molecules. Moreover, the downregulation of NDRG2 expression by long‐term stress‐induced methylation is directly correlated with the development of ATLL and other cancers. Thus, NDRG2 might be important for the development of stress‐induced leukemia and other cancers and has become an important target for novel molecular therapies. In tumor cells, the loss of NDRG2 expression induces constitutive phosphorylation of PTEN C‐terminal, which maintains PTEN in an inactive closed conformation and leads to constitutive AKT activation.
登录
查看更多内容
热疗诱导的 NDRG2 上调通过抑制 ERK1/2 信号通路抑制人肝细胞癌的侵袭
影响因子：
3.7
作者：
Guo Y;Ma J;Wu L;Wang Q;Li X;Li X;Zhang Y;Zhang J;Yao L;Zhang J;Liu W
通讯作者：
Liu W
影响因子：
25.7
作者：
Lee, Dong Gwang;Lee, Sang-Hyun;Min, Jeong-Ki
通讯作者：
Min, Jeong-Ki
影响因子：
3.7
作者：
Li R;Yu C;Jiang F;Gao L;Li J;Wang Y;Beckwith N;Yao L;Zhang J;Wu G
通讯作者：
Wu G
影响因子：
4.8
作者：
Kokame, K;Kato, H;Miyata, T
通讯作者：
Miyata, T
影响因子：
20.3
作者：
Hidaka, Tomonori;Nakahata, Shingo;Morishita, Kazuhiro
通讯作者：
Morishita, Kazuhiro