TRAF6 Stimulates the Tumor-Promoting Effects of TGF-β Type I Receptor Through Polyubiquitination and Activation of Presenilin 1

Gudey et al. Sci. Signal. 2014; 7: ra2.

Speaker: Yi-Hsin Hsiao (蕭宜馨)             Time: 13:10~14:00, June 10, 2015

Commentator: Dr. Li-Jin Hsu (徐麗君 老師)   Place: Room 601

Abstract:

Transforming growth factor β (TGFβ) is a cytokine which plays a multifunctional role in different cellular responses, such as proliferation, epithelial-mesenchymal transition (EMT), and migration. The authors previously reported that tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), a ubiquitin E3 ligase, can ubiquitinate TGFβ type I receptor (TβRI) and generate a nuclear translocational intracellular domain (ICD) of TβRI upon TGFβ stimulation. However, it is still unclear how TβRI-ICD is released from the cell membrane. In the present study, the authors showed that TGFβ activated presenilin (PS1), a transmembrane protein that is the catalytic subunit of the γ-secretase complex, to generate N-terminal (NTF; 27 to 28 kD) and C-terminal (CTF; 16 to 17 kD) fragments. Moreover, TRAF6 caused Lys63-linked polyubiquitination of PS1-NTF and TβRI. These modifications were essential for the ability of γ-secretase to cleave TβRI in the transmembrane region, which generated the TβRI-ICD. In addition, TGFβ- and γ-secretase-induced TβRI processing between valine-129 and isoleucine-130 occurred at the plasma membrane. TβRI-ICD after entering the nucleus bound to the promoter of TβRI and increased the transcription of TβRI, Snail and Jag, which resulted in enhancing the invasiveness of tumor cells. Furthermore, treatment with γ-secretase inhibitors prevented the growth of prostate tumor xenografts. Therefore, these results suggest that γ-secretase inhibitors may be a novel therapeutic target for prostate cancer and other cancers.

References

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