Upon activation by various stimuli, PI3K/AKT or similar effectors can relieve the inhibitory effect of the TSC1/TSC2 complex through their phosphorylation to favor mTOR/S6K activation in the downstream. | Turkish Journal of Biology Turk J Biol (2018) 42: 268-278 © TÜBİTAK doi: Research Article IKBKE inhibits TSC1 to activate the mTOR/S6K pathway for oncogenic transformation 1,2,3, Serkan İsmail GÖKTUNA * Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey 2 National Nanotechnology Research Center (UNAM), Bilkent University, Ankara, Turkey 3 Laboratory of Medical Chemistry, Interdisciplinary Genomics and Genoproteomics Research Center (GIGA), University of Liege, Liege, Belgium 1 Received: Accepted/Published Online: Final Version: Abstract: IKBKE (IKKε) has emerged as a key modulator of multiple substrates, controlling oncogenic pathways in various malignancies. mTOR signaling, required for cellular growth, proliferation, and vascular angiogenesis in cancer, is potentially one of the pathways regulated by IKKε. Upon activation by various stimuli, PI3K/AKT or similar effectors can relieve the inhibitory effect of the TSC1/TSC2 complex through their phosphorylation to favor mTOR/S6K activation in the downstream. Therefore, any activity that interferes with PI3K/AKT or their downstream targets, such as TSC1/2 or GSK3α/β, may activate the mTOR/S6K pathway for oncogenic transformation in normal cells. Previous studies have shown that PI3K/AKT can be directly phosphoregulated by IKKε. Here, we propose a new regulatory function for IKKε in the mTOR/S6K pathway through its direct interaction with TSC1, leading to TSC1 phosphorylation, which is vital to suppress its inhibitory role in mTOR activation. Experimentally, upon IKKε deficiency in colorectal cancer cells, we observed that S6K activity was diminished while TSC1 levels were found to be stabilized. We hypothesized that these observations may result from direct interaction between IKKε and TSC1. Indeed, the interaction of these two proteins involves the phosphoregulation .
