title: Involvement of TGFβ-induced phosphorylation of the PTEN C-terminus on TGFβ-induced acquisition of malignant phenotypes in lung cancer cells.
abstract: Transforming growth factor β (TGFβ) derived from the tumor microenvironment induces malignant phenotypes such as epithelial-mesenchymal transition (EMT) and aberrant cell motility in lung cancers. TGFβ-induced translocation of β-catenin from E-cadherin complexes into the cytoplasm is involved in the transcription of EMT target genes. PTEN (phosphatase and tensin homologue deleted from chromosome 10) is known to exert phosphatase activity by binding to E-cadherin complexes via β-catenin, and recent studies suggest that phosphorylation of the PTEN C-terminus tail might cause loss of this PTEN phosphatase activity. However, whether TGFβ can modulate both β-catenin translocation and PTEN phosphatase activity via phosphorylation of the PTEN C-terminus remains elusive. Furthermore, the role of phosphorylation of the PTEN C-terminus in TGFβ-induced malignant phenotypes has not been evaluated. To investigate whether modulation of phosphorylation of the PTEN C-terminus can regulate malignant phenotypes, here we established lung cancer cells expressing PTEN protein with mutation of phosphorylation sites in the PTEN C-terminus (PTEN4A). We found that TGFβ stimulation yielded a two-fold increase in the phosphorylated -PTEN/PTEN ratio. Expression of PTEN4A repressed TGFβ-induced EMT and cell motility even after snail expression. Our data showed that PTEN4A might repress EMT through complete blockade of β-catenin translocation into the cytoplasm, besides the inhibitory effect of PTEN4A on TGFβ-induced activation of smad-independent signaling pathways. In a xenograft model, the tumor growth ratio was repressed in cells expressing PTEN4A. Taken together, these data suggest that phosphorylation sites in the PTEN C-terminus might be a therapeutic target for TGFβ-induced malignant phenotypes in lung cancer cells.
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Aoyama
authors.forename: Naozumi
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Koji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohnoh
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kusunose
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kimura
authors.forename: Ryo
authors.initials: R
authors.lastname: Ogata
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawabe
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D047368:Tumor Burden
chemical_list: D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051059:PTEN Phosphohydrolase