Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis.
Bottom Line: The protein products of the tuberous sclerosis complex (TSC) genes, TSC1 and TSC2, form a complex, which inhibits the small G-protein, Ras homolog enriched in brain (Rheb).The vast majority of research regarding these proteins has focused on mammalian Target of Rapamycin (mTOR), a target of Rheb.We present evidence that such non-canonical functions of the TSC-Rheb signalling network exist, propose a standard of evidence for these non-canonical functions, and discuss their potential clinical and therapeutic implications for patients with TSC and lymphangioleiomyomatosis (LAM).
Affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.Show MeSH
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Mentions: The primary cilium consists of a finger-like plasma membrane projection, reinforced by an internal stalk of microtubule bundles with a centriole anchoring its base (Goetz & Anderson, 2010). These cilia transmit signals about extracellular flow and are epicenters for certain signal transduction pathways such as Hedgehog signalling. TSC1 is present at the base of the primary cilium in cultured human retinal pigmented and kidney epithelial cells (Fig 4; Astrinidis et al, 2006; Hartman et al, 2009). Interestingly, Tsc1−/− and Tsc2−/− mouse embryonic fibroblasts (MEFs) have longer cilia, and a greater percentage of cells in culture are single- or multi-ciliated compared to wild-type (WT) MEFs, suggesting that the TSC1/TSC2 complex suppresses cilia formation (Hartman et al, 2009). Importantly, Rapamycin treatment restores cilia length in some, but not all, cell lines tested, and it does not reduce the frequency of ciliation in MEFs. Taken together, this could indicate that non-canonical functions of TSC1 and TSC2 are important for ciliary phenotypes.
Affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.