title: Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis.
abstract: Tuberous sclerosis is an autosomal dominant human genetic disorder in which distinctive tumors called hamartomas develop. Germline mutations in either TSC1 or TSC2 cause this syndrome, and hamartomas typically display second hit events with loss of the remaining normal allele. Studies initiated in Drosophila have identified a role for the Tsc1 and Tsc2 genes in the regulation of cell and organ size, and genetic interaction studies have placed them in the PI3K-Akt-mTOR-S6K pathway. Biochemical studies have shown that activated Akt phosphorylates TSC2 in the TSC1/TSC2 protein complex, inactivating it; while TSC1/TSC2 has GAP activity for the Rheb GTPase (a member of the ras family), and activated Rheb-GTP activates mTOR. Thus, in cells lacking TSC1 or TSC2 there are increased levels of Rheb-GTP which leads to activation of mTOR, leading to cell size increase and growth. These developments provide enhanced understanding of this signaling pathway and fundamental insights into the pathogenesis of tuberous sclerosis, and open the possibility of treatment for hamartomas by several pharmacologic approaches.
authors: Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. dk@rics.bwh.harvard.edu
authors: David J
authors: DJ
authors: Kwiatkowski
mesh_terms: D029721:Drosophila Proteins; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000502:physiology*; D000076205:Ras Homolog Enriched in Brain Protein; D012097:Repressor Proteins / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D029721:Drosophila Proteins; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D011506:Proteins; D000076205:Ras Homolog Enriched in Brain Protein; D012097:Repressor Proteins; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C490211:RHEB protein, human; C490212:Rheb protein, Drosophila; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C546842:MTOR protein, human