Shingo Nakahata 1 , 13 , Tomonaga Ichikawa 1 , 13 , Phudit Maneesaay 2 , Yusuke Saito 1 , Kentaro Nagai 1 , Tomohiro Tamura 1 , Nawin Manachai 1 , Norio Yamakawa 1 , Makoto Hamasaki 1 , Issay Kitabayashi 3 , Yasuhito Arai 4 , Yae Kanai 5 , Tomohiko Taki 6 , Takaya Abe 7 , Hiroshi Kiyonari 7 , Kazuya Shimoda 8 , Koichi Ohshima 9 , Akira Horii 10 , Hiroshi Shima 11 , Masafumi Taniwaki 12 , Ryoji Yamaguchi 2 , Kazuhiro Morishita a , 1
26 February 2014
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.
The PI3K pathway that encompasses the tumour suppressor PTEN contributes to tumourigenesis in adult T-cell leukaemia-lymphoma (ATLL). In this study, Nakahata et al. show that PTEN is dephosphorylated by NDRG2, and that loss of NDGR2 in ATLL results in the activation of the PI3K pathway.