Direct regulation of transforming growth factor β‐induced epithelial–mesenchymal transition by the protein phosphatase activity of unphosphorylated PTEN in lung cancer cells

Cancer Science

Masaaki Kusunose³  Naozumi Hashimoto³  Motohiro Kimura³  Ryo Ogata³  Daisuke Aoyama³  Koji Sakamoto³  Shinichi Miyazaki³  Akira Ando³  Norihito Omote³  Kazuyoshi Imaizumi¹  Tsutomu Kawabe² 

[1] Department of Respiratory Medicine and Allergy, Fujita Health University, Toyoake, Japan;Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

关键词: β‐Catenin;    epithelial–mesenchymal transition;    protein phosphatase activity;    PTEN;    transforming growth factor β;   

DOI  :  10.1111/cas.12831

来源: Wiley

【 摘 要 】

Abstract

Transforming growth factor β (TGFβ) causes the acquisition of epithelial–mesenchymal transition (EMT). Although the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) can negatively regulate many signaling pathways activated by TGFβ, hyperactivation of these signaling pathways is observed in lung cancer cells. We recently showed that PTEN might be subject to TGFβ-induced phosphorylation of its C-terminus, resulting in a loss of its enzyme activities; PTEN with an unphosphorylated C-terminus (PTEN4A), but not PTEN wild, inhibits TGFβ-induced EMT. Nevertheless, whether or not the blockade of TGFβ-induced EMT by the PTEN phosphatase activity might be attributed to the unphosphorylated PTEN C-terminus itself has not been fully determined. Furthermore, the lipid phosphatase activity of PTEN is well characterized, whereas the protein phosphatase activity has not been determined. By using lung cancer cells carrying PTEN domain deletions or point mutants, we investigated the role of PTEN protein phosphatase activities on TGFβ-induced EMT in lung cancer cells. The unphosphorylated PTEN C-terminus might not directly retain the phosphatase activities and repress TGFβ-induced EMT; the modification that keeps the PTEN C-terminus not phosphorylated might enable PTEN to retain the phosphatase activity. PTEN4A with G129E mutation, which lacks lipid phosphatase activity but retains protein phosphatase activity, repressed TGFβ-induced EMT. Furthermore, the protein phosphatase activity of PTEN4A depended on an essential association between the C2 and phosphatase domains. These data suggest that the protein phosphatase activity of PTEN with an unphosphorylated C-terminus might be a therapeutic target to negatively regulate TGFβ-induced EMT in lung cancer cells.

【 授权许可】

CC BY-NC-ND   
© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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