Loss of NDRG2 enhanced activation of the NF-κB pathway by PTEN and NIK phosphorylation for ATL and other cancer development.
Loss of NDRG2 enhanced activation of the NF-κB pathway by PTEN and NIK phosphorylation for ATL and other cancer development.
复制标题
DOI：
10.1038/srep12841
复制
发表时间：
2015-08-13
影响因子：
4.6
通讯作者：
Morishita K
中科院分区：
文献类型：
--
作者：
Ichikawa T;Nakahata S;Fujii M;Iha H;Morishita K
核因子-κB信号的激活在成人T细胞白血病/淋巴瘤和许多其他癌症的发生发展中起着核心作用。然而，对NF-κB通路的激活机制仍知之甚少。最近，我们报道了N-myc下游调节基因2(NDRG2)是磷脂酰肌醇3-激酶(PI3K)/AKT通路的负调控因子，它通过PP2A的募集促进PTEN在其C末端的活性去磷酸化形式。此外，NDRG2的表达下调促进了PTEN的非活性磷酸化形式，从而导致在各种类型的癌细胞中结构性地激活PI3K/AKT信号。在这里，我们研究了NDRG2在调节NF-κB信号中的作用。NDRG2在ATL细胞中的强制表达不仅通过抑制AKT信号通路下调经典通路，而且通过PP2A的募集诱导NF-κB诱导激酶(NIK)去磷酸化而下调非典型通路。因此，NDRG2不仅可以抑制PI3K/AKT信号通路，还可以抑制在宿主防御或免疫应答中对人类T细胞白血病病毒1型感染的免疫应答中的NF-κB信号通路。此外，NDRG2的表达缺失可能在HTLV-1感染后肿瘤的发展过程中起重要作用。
The activation of nuclear factor kappa B (NF-κB) signaling has a central role in the development of adult T-cell leukemia/lymphoma (ATL) and many other cancers. However, the activation mechanism of the NF-κB pathways remains poorly understood. Recently, we reported that N-myc downstream-regulated gene 2 (NDRG2) is a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT pathway by promoting the active dephosphorylated form of PTEN at its C-terminus via the recruitment of PP2A. Additionally, the down-regulation of NDRG2 expression promotes the inactive phosphorylated form of PTEN, which results in constitutively active PI3K/AKT signaling in various cancer cell types. Here, we investigated the involvement of NDRG2 in modulating NF-κB signaling. The forced expression of NDRG2 in ATL cells down-regulates not only the canonical pathway by inhibiting AKT signaling but also the non-canonical pathway by inducing NF-κB-inducing kinase (NIK) dephosphorylation via the recruitment of PP2A. Therefore, NDRG2 works as a PP2A recruiter to suppress not only PI3K/AKT signaling but also NF-κB signaling, which is particularly important in host defenses or immune responses to Human T-cell leukemia virus type 1 (HTLV-1) infection. Furthermore, the loss of NDRG2 expression might play an important role in the progression of tumor development after HTLV-1 infection.