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 Taniwaki, Ryoji Yamaguchi and Kazuhiro Morishita ()
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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

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4393

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