Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 10, Pages 4099-4112Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.769109
Keywords
-
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Takeda Science Foundation
- Smoking Research Foundation
- Daiichi-Sankyo Foundation of Life Science
- Naito Foundation
- Vehicle Racing Commemorative Foundation
- MEXT
- Showa Pharmaceutical University
- Medical Research Institute, Tokyo Medical and Dental University
- Japan Society for the Promotion of Science
- [15K18866]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available