Syntenin regulates TGF-[beta]1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-[beta] type I receptor internalization

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)-[beta]1-mediated Smad activation and the epithelial-to-mesenchymal transition (EMT) by preventing caveolin-1-mediated internalization of TGF-[beta] type I receptor (T[beta]RI). Knockdown of syntenin suppressed TGF-[beta]1-mediated cell migration, transcriptional responses and Smad2/3 activation in various types of cells; however, overexpression of syntenin facilitated TGF-[beta]1-mediated responses. In particular, syntenin knockdown abolished both the basal and TGF-[beta]1-mediated repression of E-cadherin expression, as well as induction of vimentin expression along with Snail and Slug upregulation; thus, blocking the TGF-[beta]1-induced EMT in A549 cells. In contrast, overexpression of syntenin exhibited the opposite effect. Knockdown of syntenin-induced ubiquitination and degradation of T[beta]RI, but not TGF-[beta] type II receptor, leading to decreased T[beta]RI expression at the plasma membrane. Syntenin associated with T[beta]RI at its C-terminal domain and a syntenin mutant lacking C-terminal domain failed to increase TGF-[beta]1-induced responses. Biochemical analyzes revealed that syntenin inhibited the interaction between caveolin-1 and T[beta]RI and knockdown of syntenin induced a massive internalization of T[beta]RI and caveolin-1 from lipid rafts, indicating that syntenin may increase TGF-[beta] signaling by inhibiting caveolin-1-dependent internalization of T[beta]RI. 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-[beta] signaling by regulating caveolin-1-mediated internalization of T[beta]RI; thus, providing a novel function for syntenin that is linked to cancer progression.