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

• Published in: Cancer science Vol. 106; no. 12; pp. 1693 - 1704
• Main Authors: Kusunose, Masaaki, Hashimoto, Naozumi, Kimura, Motohiro, Ogata, Ryo, Aoyama, Daisuke, Sakamoto, Koji, Miyazaki, Shinichi, Ando, Akira, Omote, Norihito, Imaizumi, Kazuyoshi, Kawabe, Tsutomu, Hasegawa, Yoshinori
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2015; John Wiley and Sons Inc
• Subjects: Blotting, Western; Cell Line, Tumor; Chromosome 10; Cytoplasm; Enzymatic activity; Epithelial-Mesenchymal Transition - physiology; epithelial–mesenchymal transition; Fluorescent Antibody Technique; Gene expression; Growth factors; Humans; Lipids; Lung cancer; Lung Neoplasms - pathology; Mesenchyme; Microscopy, Confocal; Original; Phosphatase; Phosphates; Phosphoprotein Phosphatases - metabolism; Phosphorylation; Protein phosphatase; protein phosphatase activity; Proteins; PTEN; PTEN Phosphohydrolase - metabolism; PTEN protein; Signal transduction; Studies; Tensin; Therapeutic applications; Transfection; Transforming growth factor; Transforming Growth Factor beta - metabolism; transforming growth factor β; Transforming growth factor-b; Tumor suppressor genes; β‐Catenin; United Kingdom > UK; United States > US; Japan; PTEN; β-Catenin; epithelial-mesenchymal transition; protein phosphatase activity; transforming growth factor β
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.12831

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. The PTEN protein phosphatase activity inhibits TGFβ‐induced EMT via the essential association of the C2 and the phosphatase domains.