Turkish Journal of Biology
DOI
10.3906/biy-1801-57
Abstract
IKBKE (IKK?) 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 IKK?. 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 GSK3?/ß, may activate the mTOR/S6K pathway for oncogenic transformation in normal cells. Previous studies have shown that PI3K/AKT can be directly phosphoregulated by IKK?. Here, we propose a new regulatory function for IKK? 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 IKK? 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 IKK? and TSC1. Indeed, the interaction of these two proteins involves the phosphoregulation of TSC1 in various cell lines. Therefore, we propose a mechanism where IKK?, through regulating TSC1 stability in cancer cells, may create an alternative regulatory loop for the activation of mTOR signaling. These results can potentially be important for the development of novel therapeutic strategies targeting mTOR signaling.
Keywords
TSC1, IKBKE (IKK?), RPS6K1 (P70-S6K1), mTOR, protein synthesis, proliferation, cancer
First Page
268
Last Page
278
Recommended Citation
GÖKTUNA, SERKAN İSMAİL
(2018)
"IKBKE inhibits TSC1 to activate the mTOR/S6K pathway for oncogenic transformation,"
Turkish Journal of Biology: Vol. 42:
No.
4, Article 2.
https://doi.org/10.3906/biy-1801-57
Available at:
https://journals.tubitak.gov.tr/biology/vol42/iss4/2