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The S/T-protein kinases activated by phosphoinositide 3-kinase (PI3K) regulate a myriad of cellular processes. Here, we show that an approach using a combination of biochemistry and bioinformatics can identify substrates of these kinases. This approach identifies the tuberous sclerosis complex-2 gene product, tuberin, as a potential target of Akt/PKB. We(More)
BACKGROUND Tuberous Sclerosis Complex (TSC) is a genetic disorder that occurs through the loss of heterozygosity of either TSC1 or TSC2, which encode Hamartin or Tuberin, respectively. Tuberin and Hamartin form a tumor suppressor heterodimer that inhibits the mammalian target of rapamycin (mTOR) nutrient signaling input, but how this occurs is unclear. (More)
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that occurs upon mutation of either the TSC1 or TSC2 genes, which encode the protein products hamartin and tuberin, respectively. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation(More)
The mammalian target of rapamycin (mTOR) integrates nutrient and mitogen signals to regulate cell growth (increased cell mass and cell size) and cell division. The immunosuppressive drug rapamycin inhibits cell cycle progression via inhibition of mTOR; however, the signaling pathways by which mTOR regulates cell cycle progression have remained poorly(More)
In mammalian cells, amino acids affect the phosphorylation state and function of several proteins involved in mRNA translation that are regulated via the rapamycin-sensitive mTOR (mammalian target of rapamycin) pathway. These include ribosomal protein S6 kinase, S6K1, and eukaryotic initiation factor 4E-binding protein, 4E-BP1. Amino acids, especially(More)
Amino acids positively regulate signaling through the mammalian target of rapamycin (mTOR). Recent work demonstrated the importance of the tuberous sclerosis protein TSC2 for regulation of mTOR by insulin. TSC2 contains a GTPase-activator domain that promotes hydrolysis of GTP bound to Rheb, which positively regulates mTOR signaling. Some studies have(More)
The phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), a potent stimulator of Erk, leads to the phosphorylation of 4E-BP1 and its dissociation from eIF4E. In contrast to agonists such as insulin, this occurs independently of PKB activation. In this report, we investigate the mechanism by which TPA regulates 4E-BP1 phosphorylation. Treatment of(More)
Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development. However, in cells expressing tuberin, it is not known how repression of mTOR signaling is relieved to activate this pathway in response to growth factors and how hamartin participates in this process. We show that(More)
Many human diseases occur when the precise regulation of cell growth (cell mass/size) and proliferation (rates of cell division) is compromised. This review highlights those human disorders that occur as a result of inappropriate cellular signal transduction through the mammalian target of rapamycin (mTOR), a major pathway that coordinates proper cell(More)
Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signalling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by peroxisomal biogenesis factors 19 and 5 (PEX19 and PEX5),(More)