Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers
نویسندگان
چکیده
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.
منابع مشابه
Loss of NDRG2 enhanced activation of the NF-κB pathway by PTEN and NIK phosphorylation for ATL and other cancer development
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 promo...
متن کاملStudy of Antimetastatic Effect of Genistein Through Inhibition of Expression of Matrix Metalloproteinase in A-549 Cell Line
The lung cancer is one of the most dangerous cancers and is also the leading cause of cancer death worldwide, accounting for about 1.3 million deaths annually. However in clinical practice, lung cancer therapies commonly do with chemotherapy, although it is hard because the lung cancer may progress to metastasis stage. The metastasis of lung cancer is highly dependent of expression of matrix me...
متن کاملAnti-diabetic effect of loganin by inhibiting FOXO1 nuclear translocation via PI3K/Akt signaling pathway in INS-1 cell
Objective(s): JiangTangXiaoKe (JTXK) granule, a Chinese traditional herbal formula, has been clinically used and demonstrated to be beneficial in controlling high glucose and to relieve the symptoms of Type 2 diabetes mellitus patients for decades. In this study, we explored how loganin, one of the components in JTXK granule, mediated the anti-diabetic effect.Materials and Methods: We generate...
متن کاملMolecular aspects of gefitinib antiproliferative and pro-apoptotic effects in PTEN-positive and PTEN-negative prostate cancer cell lines.
To date, no effective therapeutic treatment allows abrogation of the progression of prostate cancer (PCa) to more invasive forms. One of the major targets for the therapy in PCa can be epidermal growth factor receptor (EGFR), which signals via the phosphoinositide 3'-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways, among others. Despite multiple reports of overexpression ...
متن کاملSpecific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer
Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and...
متن کامل