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

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  • Shingo Nakahata

    (University of Miyazaki, 5200 Kihara, Kiyotake)

  • Tomonaga Ichikawa

    (University of Miyazaki, 5200 Kihara, Kiyotake)

  • Phudit Maneesaay

    (University of Miyazaki, Nishi 1-1, Gakuen Kibana Dai)

  • Yusuke Saito

    (University of Miyazaki, 5200 Kihara, Kiyotake)

  • Kentaro Nagai

    (University of Miyazaki, 5200 Kihara, Kiyotake)

  • Tomohiro Tamura

    (University of Miyazaki, 5200 Kihara, Kiyotake)

  • Nawin Manachai

    (University of Miyazaki, 5200 Kihara, Kiyotake)

  • Norio Yamakawa

    (University of Miyazaki, 5200 Kihara, Kiyotake)

  • Makoto Hamasaki

    (University of Miyazaki, 5200 Kihara, Kiyotake)

  • Issay Kitabayashi

    (National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku)

  • Yasuhito Arai

    (National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku)

  • Yae Kanai

    (National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku)

  • Tomohiko Taki

    (Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku)

  • Takaya Abe

    (Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe)

  • Hiroshi Kiyonari

    (Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe)

  • Kazuya Shimoda

    (University of Miyazaki, 5200 Kihara, Kiyotake)

  • Koichi Ohshima

    (School of Medicine, Kurume University, 67 Asahimati)

  • Akira Horii

    (Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku)

  • Hiroshi Shima

    (Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiode)

  • Masafumi Taniwaki

    (Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku)

  • Ryoji Yamaguchi

    (University of Miyazaki, Nishi 1-1, Gakuen Kibana Dai)

  • Kazuhiro Morishita

    (University of Miyazaki, 5200 Kihara, Kiyotake)

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.

Suggested Citation

  • Shingo Nakahata & Tomonaga Ichikawa & Phudit Maneesaay & Yusuke Saito & Kentaro Nagai & Tomohiro Tamura & Nawin Manachai & Norio Yamakawa & Makoto Hamasaki & Issay Kitabayashi & Yasuhito Arai & Yae Ka, 2014. "Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers," Nature Communications, Nature, vol. 5(1), pages 1-15, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4393
    DOI: 10.1038/ncomms4393
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