TMED10 Protein Interferes with Transforming Growth Factor (TGF)-β Signaling by Disrupting TGF-β Receptor Complex Formation

The intensity and duration of TGF-beta signaling determine the cellular biological response. How this is negatively regulated is not well understood. Here, we identified a novel negative regulator of TGF-beta signaling, transmembrane p24-trafficking protein 10 (TMED10). TMED10 disrupts the complex formation between TGF-beta type I (also termed ALK5) and type II receptors (T beta RII). Misexpression studies revealed that TMED10 attenuated TGF-beta-mediated signaling. A 20-amino acid-long region from Thr(91) to Glu(110) within the extracellular region of TMED10 was found to be crucial for TMED 10 interaction with both ALK5 and T beta RII. Synthetic peptides corresponding to this region inhibit both TGF-beta-induced Smad2 phosphorylation and Smad-dependent transcriptional reporter activity. In a xenograft cancer model, where previously TGF-beta was shown to elicit tumor-promoting effects, gain-of-function and loss-of-function studies for TMED10 revealed a decrease and increase in the tumor size, respectively. Thus, we determined herein that TMED10 expression levels are the key determinant for efficiency of TGF-beta receptor complex formation and signaling.