| First Author | Gudey SK | Year | 2014 |
| Journal | Sci Signal | Volume | 7 |
| Issue | 307 | Pages | ra2 |
| PubMed ID | 24399296 | Mgi Jnum | J:259786 |
| Mgi Id | MGI:6142747 | Doi | 10.1126/scisignal.2004207 |
| Citation | Gudey SK, et al. (2014) TRAF6 stimulates the tumor-promoting effects of TGFbeta type I receptor through polyubiquitination and activation of presenilin 1. Sci Signal 7(307):ra2 |
| abstractText | Transforming growth factor-beta (TGFbeta) can be both a tumor promoter and suppressor, although the mechanisms behind the protumorigenic switch remain to be fully elucidated. The TGFbeta type I receptor (TbetaRI) is proteolytically cleaved in the ectodomain region. Cleavage requires the combined activities of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF-alpha-converting enzyme (TACE). The cleavage event occurs selectively in cancer cells and generates an intracellular domain (ICD) of TbetaRI, which enters the nucleus to mediate gene transcription. Presenilin 1 (PS1), a gamma-secretase catalytic core component, mediates intramembrane proteolysis of transmembrane receptors, such as Notch. We showed that TGFbeta increased both the abundance and activity of PS1. TRAF6 recruited PS1 to the TbetaRI complex and promoted lysine-63-linked polyubiquitination of PS1, which activated PS1. Furthermore, PS1 cleaved TbetaRI in the transmembrane domain between valine-129 and isoleucine-130, and ICD generation was inhibited when these residues were mutated to alanine. We also showed that, after entering the nucleus, TbetaRI-ICD bound to the promoter and increased the transcription of the gene encoding TbetaRI. The TRAF6- and PS1-induced intramembrane proteolysis of TbetaRI promoted TGFbeta-induced invasion of various cancer cells in vitro. Furthermore, when a mouse xenograft model of prostate cancer was treated with the gamma-secretase inhibitor DBZ {(2S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dib enzo[b,d]azepin-7-yl)-propionamide}, generation of TbetaRI-ICD was prevented, transcription of the gene encoding the proinvasive transcription factor Snail1 was reduced, and tumor growth was inhibited. These results suggest that gamma-secretase inhibitors may be useful for treating aggressive prostate cancer. |
