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; Kazuhiro Morishita

doi:10.1038/ncomms4393

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

Nat Commun. 2014 Feb 26:5:3393. doi: 10.1038/ncomms4393.

Authors

Shingo Nakahata¹, Tomonaga Ichikawa¹, Phudit Maneesaay², Yusuke Saito³, Kentaro Nagai³, Tomohiro Tamura³, Nawin Manachai³, Norio Yamakawa³, Makoto Hamasaki³, Issay Kitabayashi⁴, Yasuhito Arai⁵, Yae Kanai⁶, Tomohiko Taki⁷, Takaya Abe⁸, Hiroshi Kiyonari⁸, Kazuya Shimoda⁹, Koichi Ohshima¹⁰, Akira Horii¹¹, Hiroshi Shima¹², Masafumi Taniwaki¹³, Ryoji Yamaguchi², Kazuhiro Morishita³

Affiliations

¹ 1] Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan [2].
² Department of Veterinary Pathology, University of Miyazaki, Nishi 1-1, Gakuen Kibana Dai, Miyazaki 889-2192, Japan.
³ Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
⁴ Division of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁵ Division of Cancer Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁶ Division of Molecular Pathology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁷ Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
⁸ Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
⁹ Department of Gastroenterology and Hematology, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
¹⁰ Department of Pathology, School of Medicine, Kurume University, 67 Asahimati, Kurume 830-0011, Japan.
¹¹ Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
¹² Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori 981-1293, Japan.
¹³ Department of Molecular Hematology and Oncology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Blotting, Western
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Jurkat Cells
Leukemia-Lymphoma, Adult T-Cell / genetics
Leukemia-Lymphoma, Adult T-Cell / metabolism
Leukemia-Lymphoma, Adult T-Cell / pathology
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Microscopy, Confocal
NIH 3T3 Cells
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / pathology
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism*
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism*
Phosphorylation
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism*
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction*
Tumor Cells, Cultured
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*

Substances

NDRG2 protein, human
Tumor Suppressor Proteins
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
PTEN protein, human

Associated data

GEO/GSE43017