Non‐canonical functions of the tuberous sclerosis complex‐Rheb signalling axis

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. Here, we propose that there are clinically relevant functions and targets of TSC1, TSC2 and Rheb, which are independent of mTOR. 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).