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

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

Research output: Contribution to journal › Article › peer-review

120 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 language	English
Article number	3393
Pages (from-to)	3393
Number of pages	1
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4393
Publication status	Published - 2014
Externally published	Yes

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms4393

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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, 3393. [3393]. https://doi.org/10.1038/ncomms4393

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, Taniwaki, M, Yamaguchi, R & Morishita, K 2014, 'Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers', Nature communications, vol. 5, 3393, pp. 3393. https://doi.org/10.1038/ncomms4393

@article{8d36691ac219426ab49d1207b8fc0d5c,

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

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. ",

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

note = "Funding Information: We thank Y. Motoyoshi, A. Nakatake and I. Morinaga for their technical assistance and N. Ishigami for secretarial assistance. We thank all of the members of the Division of Tumor and Cellular Biochemistry and HTLV-1/ATL Research Facility, University of Miyazaki for helpful discussions and comments. Also, we gratefully thank all of the researchers, who kindly provided us their important cell lines and materials. This work was supported by Grant-in-Aid for Scientific Research on Priority Areas (20012043) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; Research fund from Miyazaki Prefecture Collaboration of Regional Entities for the Advancement of Technological Excellence (60G01-B7002022), Japan Science and Technology Agency (JST); Scientific Research (B) (21390098) (KM); and Young Scientists (B) (23701061 to SN and 23790372 to TI) of Japan Society for the Promotion of Science (JSPS).",

year = "2014",

doi = "10.1038/ncomms4393",

language = "English",

volume = "5",

pages = "3393",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers

AU - Nakahata, Shingo

AU - Ichikawa, Tomonaga

AU - Maneesaay, Phudit

AU - Saito, Yusuke

AU - Nagai, Kentaro

AU - Tamura, Tomohiro

AU - Manachai, Nawin

AU - Yamakawa, Norio

AU - Hamasaki, Makoto

AU - Kitabayashi, Issay

AU - Arai, Yasuhito

AU - Kanai, Yae

AU - Taki, Tomohiko

AU - Abe, Takaya

AU - Kiyonari, Hiroshi

AU - Shimoda, Kazuya

AU - Ohshima, Koichi

AU - Horii, Akira

AU - Shima, Hiroshi

AU - Taniwaki, Masafumi

AU - Yamaguchi, Ryoji

AU - Morishita, Kazuhiro

N1 - Funding Information: We thank Y. Motoyoshi, A. Nakatake and I. Morinaga for their technical assistance and N. Ishigami for secretarial assistance. We thank all of the members of the Division of Tumor and Cellular Biochemistry and HTLV-1/ATL Research Facility, University of Miyazaki for helpful discussions and comments. Also, we gratefully thank all of the researchers, who kindly provided us their important cell lines and materials. This work was supported by Grant-in-Aid for Scientific Research on Priority Areas (20012043) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; Research fund from Miyazaki Prefecture Collaboration of Regional Entities for the Advancement of Technological Excellence (60G01-B7002022), Japan Science and Technology Agency (JST); Scientific Research (B) (21390098) (KM); and Young Scientists (B) (23701061 to SN and 23790372 to TI) of Japan Society for the Promotion of Science (JSPS).

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms4393

DO - 10.1038/ncomms4393

M3 - Article

C2 - 24569712

AN - SCOPUS:84919702854

SN - 2041-1723

VL - 5

SP - 3393

JO - Nature Communications

JF - Nature Communications

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ER -

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

Abstract

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UN SDGs

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