Sci. Signal., 7 January 2014
Blocking Oncogenic Receptor CleavageThe 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 -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 -secretase inhibitor decreased the production of the intracellular domain of the TGFβ receptor and tumor growth. Thus, blocking -secretase activity could attenuate the tumor-promoting effects of TGFβ signaling and decrease the growth of prostate tumors.
Citation: S. K. Gudey, R. Sundar, Y. Mu, A. Wallenius, G. Zang, A. Bergh, C.-H. Heldin, M. Landström, TRAF6 Stimulates the Tumor-Promoting Effects of TGFβ Type I Receptor Through Polyubiquitination and Activation of Presenilin 1. Sci. Signal. 7, ra2 (2014).
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