Indexed on: 25 Jan '17Published on: 25 Jan '17Published in: Journal of Biological Chemistry
The intensity and duration of transforming growth factor (TGF)-βsignaling determine the cellular biological response. How this is negatively regulated is not well understood. Here, we identified a novel negative regulator of TGF-β signaling, transmembrane p24 trafficking protein10 (TMED10). TMED10 disrupts the complex formation between TGF-β type I (also termed ALK5) and type II receptors (TβRII). Misexpression studies revealed that TMED10 attenuated TGF-β-mediated signaling. A 20 amino acid-long region from Thr91 to Glu110 within the extracellular region of TMED10 was found to be crucial for TMED10 interaction with both ALK5 and TβRII. Synthetic peptides corresponding to this region inhibit both TGF-β-induced Smad2 phosphorylation and Smad-dependent transcriptional reporter activity. In a xenograft cancer model, where previously TGF-β was shown to elicit tumor-promoting effects, gain-of-function and loss-of-function studies for TMED10 revealed the decrease and increase of the tumor size, respectively. Thus, we herein determined that TMED10 expression levels are the key determinant for efficiency of TGF-β receptor complex formation and signaling.