Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins.
Mutations in the TSC1 or TSC2 genes cause tuberous sclerosis, a benign tumour syndrome in humans. Tsc2 possesses a domain that shares homology with the GTPase-activating protein (GAP) domain of Rap1-GAP, suggesting that a GTPase might be the physiological target of Tsc2. Here we show that the small GTPase Rheb (Ras homologue enriched in brain) is a direct target of Tsc2 GAP activity both in vivo and in vitro. Point mutations in the GAP domain of Tsc2 disrupted its ability to regulate Rheb without affecting the ability of Tsc2 to form a complex with Tsc1. Our studies identify Rheb as a molecular target of the TSC tumour suppressors.
Zhang
Yong
Y
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9040, USA.
Gao
Xinsheng
X
Saucedo
Leslie J
LJ
Ru
Binggen
B
Edgar
Bruce A
BA
Pan
Duojia
D
D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D019204:GTP-Binding Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000502:physiology; D015966:Gene Expression Regulation, Fungal; D016153:Genes, Suppressor; D005982:Glutathione Transferase / Q000378:metabolism; D066298:In Vitro Techniques; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017354:Point Mutation; D011494:Protein Kinases; D011506:Proteins / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
D029721:Drosophila Proteins; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins; D005982:Glutathione Transferase; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D011506:Proteins; D000076205:Ras Homolog Enriched in Brain Protein; D011993:Recombinant Fusion Proteins; 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; C490212:Rheb protein, Drosophila; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C416303:target of rapamycin protein, Drosophila