Syntenin regulates TGF-β1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-β type I receptor internalization

• Published in: Oncogene Vol. 35; no. 3; pp. 389 - 401
• Main Authors: Hwangbo, C, Tae, N, Lee, S, Kim, O, Park, O K, Kim, J, Kwon, S-H, Lee, J-H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-01-2016; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/51; 13/95; 14/105; 14/19; 38/1; 631/67/395; 631/80/84; 631/80/86/2368; 64/60; Apoptosis; Bone morphogenetic proteins; Care and treatment; Caveolin 1 - genetics; Caveolin 1 - metabolism; Cell Biology; Cell Line, Tumor; Cell Movement - genetics; Complications and side effects; Development and progression; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Human Genetics; Humans; Influence; Internal Medicine; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Oncology; original-article; Phosphorylation; Protein-Serine-Threonine Kinases - biosynthesis; Protein-Serine-Threonine Kinases - genetics; Receptors, Transforming Growth Factor beta - biosynthesis; Receptors, Transforming Growth Factor beta - genetics; Signal Transduction; Smad2 Protein - genetics; Stem cell research; Syntenins - genetics; Syntenins - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Ubiquitination; South Korea
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.100

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.