Research ArticleCancer

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

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Science Signaling  07 Jan 2014:
Vol. 7, Issue 307, pp. ra2
DOI: 10.1126/scisignal.2004207

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Blocking Oncogenic Receptor Cleavage

The surface receptor for transforming growth factor–β (TGFβ) can be cleaved, generating a fragment of the receptor containing the intracellular domain that enters the nucleus and mediates transcription of genes that encode tumor-promoting factors. Gudey et al. found that presenilin 1, a component of the γ-secretase complex, which cleaves various transmembrane proteins, also targeted the TGFβ receptor. TGFβ treatment increased the abundance and activity of presenilin 1 and the production of the receptor intracellular domain, which transcriptionally activated genes involved in invasion and metastasis. Treatment of mice bearing tumors formed from prostate cancer cells with a γ-secretase inhibitor decreased the production of the intracellular domain of the TGFβ receptor and tumor growth. Thus, blocking γ-secretase activity could attenuate the tumor-promoting effects of TGFβ signaling and decrease the growth of prostate tumors.