title: Syntenin regulates TGF-β1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-β type I receptor internalization.
abstract: Syntenin, a tandem PDZ domain containing scaffold protein, functions as a positive regulator of cancer cell progression in several human cancers. We report here that syntenin positively regulates transforming growth factor (TGF)-β1-mediated Smad activation and the epithelial-to-mesenchymal transition (EMT) by preventing caveolin-1-mediated internalization of TGF-β type I receptor (TβRI). Knockdown of syntenin suppressed TGF-β1-mediated cell migration, transcriptional responses and Smad2/3 activation in various types of cells; however, overexpression of syntenin facilitated TGF-β1-mediated responses. In particular, syntenin knockdown abolished both the basal and TGF-β1-mediated repression of E-cadherin expression, as well as induction of vimentin expression along with Snail and Slug upregulation; thus, blocking the TGF-β1-induced EMT in A549 cells. In contrast, overexpression of syntenin exhibited the opposite effect. Knockdown of syntenin-induced ubiquitination and degradation of TβRI, but not TGF-β type II receptor, leading to decreased TβRI expression at the plasma membrane. Syntenin associated with TβRI at its C-terminal domain and a syntenin mutant lacking C-terminal domain failed to increase TGF-β1-induced responses. Biochemical analyzes revealed that syntenin inhibited the interaction between caveolin-1 and TβRI and knockdown of syntenin induced a massive internalization of TβRI and caveolin-1 from lipid rafts, indicating that syntenin may increase TGF-β signaling by inhibiting caveolin-1-dependent internalization of TβRI. Moreover, a positive correlation between syntenin expression and phospho-Smad2 levels is observed in human lung tumors. Taken together, these findings demonstrate that syntenin may act as an important positive regulator of TGF-β signaling by regulating caveolin-1-mediated internalization of TβRI; thus, providing a novel function for syntenin that is linked to cancer progression.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea.
authors.forename: C
authors.initials: C
authors.lastname: Hwangbo
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea.
authors.forename: N
authors.initials: N
authors.lastname: Tae
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea.
authors.forename: O
authors.initials: O
authors.lastname: Kim
authors.affiliation: Division of Bio-imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, Gangwon-Do, Republic of Korea.
authors.forename: O K
authors.initials: OK
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Bio-imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, Gangwon-Do, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Lee
mesh_terms: D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics; D053676:Syntenins / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D051242:Caveolin 1; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053676:Syntenins; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II