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

초록

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.

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