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      Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers

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          Abstract

          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.

          Abstract

          The PI3K pathway that encompasses the tumour suppressor PTEN contributes to tumourigenesis in adult T-cell leukaemia-lymphoma (ATLL). In this study, Nakahata et al. show that PTEN is dephosphorylated by NDRG2, and that loss of NDGR2 in ATLL results in the activation of the PI3K pathway.

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          Most cited references 49

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          PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

          Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.
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            Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis.

            The tumour-suppressor phosphatase with tensin homology (PTEN) is the most important negative regulator of the cell-survival signalling pathway initiated by phosphatidylinositol 3-kinase (PI3K). Although PTEN is mutated or deleted in many tumours, deregulation of the PI3K-PTEN network also occurs through other mechanisms. Crosstalk between the PI3K pathways and other tumorigenic signalling pathways, such as those that involve Ras, p53, TOR (target of rapamycin) or DJ1, can contribute to this deregulation. How does the PI3K pathway integrate signals from numerous sources, and how can this information be used in the rational design of cancer therapies?
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              Ubiquitination regulates PTEN nuclear import and tumor suppression.

              The PTEN tumor suppressor is frequently affected in cancer cells, and inherited PTEN mutation causes cancer-susceptibility conditions such as Cowden syndrome. PTEN acts as a plasma-membrane lipid-phosphatase antagonizing the phosphoinositide 3-kinase/AKT cell survival pathway. However, PTEN is also found in cell nuclei, but mechanism, function, and relevance of nuclear localization remain unclear. We show that nuclear PTEN is essential for tumor suppression and that PTEN nuclear import is mediated by its monoubiquitination. A lysine mutant of PTEN, K289E associated with Cowden syndrome, retains catalytic activity but fails to accumulate in nuclei of patient tissue due to an import defect. We identify this and another lysine residue as major monoubiquitination sites essential for PTEN import. While nuclear PTEN is stable, polyubiquitination leads to its degradation in the cytoplasm. Thus, we identify cancer-associated mutations of PTEN that target its posttranslational modification and demonstrate how a discrete molecular mechanism dictates tumor progression by differentiating between degradation and protection of PTEN.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                26 February 2014
                : 5
                Affiliations
                [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
                [3 ]Division of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku , Tokyo 104-0045, Japan
                [4 ]Division of Cancer Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku , Tokyo 104-0045, Japan
                [5 ]Division of Molecular Pathology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku , Tokyo 104-0045, Japan
                [6 ]Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku , Kyoto 602-8566, Japan
                [7 ]Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe , Hyogo 650-0047, Japan
                [8 ]Department of Gastroenterology and Hematology, University of Miyazaki, 5200 Kihara, Kiyotake , Miyazaki 889-1692, Japan
                [9 ]Department of Pathology, School of Medicine, Kurume University, 67 Asahimati , Kurume 830-0011, Japan
                [10 ]Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku , Sendai 980-8575, Japan
                [11 ]Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiode , Natori 981-1293, Japan
                [12 ]Department of Molecular Hematology and Oncology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku , Kyoto 602-8566, Japan
                [13 ]These authors contributed equally to this work
                Author notes
                Article
                ncomms4393
                10.1038/ncomms4393
                3948061
                24569712
                Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
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