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

Shingo Nakahata, Tomonaga Ichikawa, Phudit Maneesaay, Yusuke Saito, Kentaro Nagai, Tomohiro Tamura, Nawin Manachai, Norio Yamakawa, Makoto Hamasaki, Issay Kitabayashi, Yasuhito Arai, Yae Kanai, Tomohiko Taki, Takaya Abe, Hiroshi Kiyonari, Kazuya Shimoda, Koichi Ohshima, Akira Horii, Hiroshi Shima, Masafumi TaniwakiRyoji Yamaguchi, Kazuhiro Morishita

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81 Citations (Scopus)

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.

Original languageEnglish
Number of pages1
JournalNature communications
Volume5
DOIs
Publication statusPublished - 2014 Jan 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Nakahata, S., Ichikawa, T., Maneesaay, P., Saito, Y., Nagai, K., Tamura, T., Manachai, N., Yamakawa, N., Hamasaki, M., Kitabayashi, I., Arai, Y., Kanai, Y., Taki, T., Abe, T., Kiyonari, H., Shimoda, K., Ohshima, K., Horii, A., Shima, H., ... Morishita, K. (2014). Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers. Nature communications, 5. https://doi.org/10.1038/ncomms4393