Tuberous Sclerosis and mTOR

Figures (click on image to enlarge)

TOP: A: FLAIR shows radial white matter migration lines B: T2 shows subependymal nodules outline lateral ventricles C and D: T1 post gad show enhancing subependymal nodules that may be degenerating to giant cell astrocytoma. E: RT kidney has a hemorrhaging angiomyolipoma

BOTTOM: A and B: Rheb mTOR pathway with and without TSC1/TSC2 inhibition. C: mTOR D: Rapamycin

Tuberous sclerosis is a genetic disorder affecting cellular differentiation and proliferation. Inheritance is autosomal dominant. Two genetic loci have been identified so far. Chromosome 9, specifically 9q34 (TSC1); Chromosome 16, specifically 16p13 (TSC2). Tuberin, the protein gene product of TSC2, was the first of the affected proteins to be isolated. Hamartin, the TSC1 second gene product, has recently been isolated and may function as a tumor suppressor. Hamartin and tuberin have been shown to have coiled coil domains that interact with each other. Hamartin and tuberin are thought to act synergistically to regulate cellular growth and differentiation via Rheb / mTOR inhibition. The deregulation in organogenesis results in tumors.


Rheb (Ras homolog enriched in brain), a novel, highly conserved member of the Ras superfamily of G-proteins, promotes cell growth. Rheb is involved in mTOR signaling. Studies show that Rheb functions downstream of the tumor suppressors Tsc1 (tuberous sclerosis 1)-Tsc2, with Tsc2 functioning as a GAP for Rheb

mTOR, the mammalian target of rapamycin (sirolimus), is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. It is a highly conserved protein from fungus to humans. A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). Kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction, the transmission of signals within the cell. The human genome contains about 500 protein kinase genes; they constitute about 2% of all eukaryotic genes.

Signal transduction involves ordered sequences of biochemical reactions inside the cell, that are carried out by enzymes and linked through second messengers Such processes are usually rapid, lasting on the order of milliseconds in the case of ion flux, to minutes for the activation of protein and lipid mediated kinase cascades. In many signal transduction processes, the number of proteins and other molecules participating in these events increases as the process emanates from the initial stimulus, resulting in a "signal cascade" and often results in a relatively small stimulus eliciting a large response.