The Ras-like GTPase Rheb has been identified as a crucial activator of mTORC1. Activation most likely requires a direct interaction between Rheb and mTOR, but the exact mechanism remains unclear. Using a panel of Rheb-deficient mouse embryonic fibroblasts (MEFs), we show that Rheb is indeed essential for the rapid increase of mTORC1 activity following stimulation with insulin or amino acids. Ho...

The mammalian target of rapamycin (mTOR) interacts with raptor to form the protein complex mTORC1 (mTOR complex 1), which plays a central role in the regulation of cell growth in response to environmental cues. Given that glucose is a primary fuel source and a biosynthetic precursor, how mTORC1 signaling is coordinated with glucose metabolism has been an important question. Here, we found that ...

TOR complex 1 (TORC1), an oligomer of the mTOR (mammalian target of rapamycin) protein kinase, its substrate binding subunit raptor, and the polypeptide Lst8/GbetaL, controls cell growth in all eukaryotes in response to nutrient availability and in metazoans to insulin and growth factors, energy status, and stress conditions. This review focuses on the biochemical mechanisms that regulate mTORC...

We first cloned Xenopus Rheb, which is generally believed as the upstream positive regulator of TOR, then created dominant negative form of Rheb (dn-Rheb), and also designed antisense morpholino oligomers of Rheb (Rheb-MO). Gain-of-functional experiment of TOR signal by microinjection of Rheb mRNA into blastomeres led the posterior defects for the embryos. FKBP38 is the direct negative regulato...

Mutations in either of two tumor suppressor genes, TSC1 or TSC2, cause tuberous sclerosis complex (TSC), a syndrome resulting in benign hamartomatous tumors and neurological disorders. Cellular growth defects and neuronal disorganization associated with TSC are believed to be due to upregulated TOR signaling. We overexpressed Rheb, an upstream regulator of TOR, in two different subsets of D. me...

We first cloned Xenopus Rheb, which is generally believed as the upstream positive regulator of TOR, then created dominant negative form of Rheb (dn-Rheb), and also designed antisense morpholino oligomers of Rheb (Rheb-MO). Gain-of-functional experiment of TOR signal by microinjection of Rheb mRNA into blastomeres led the posterior defects for the embryos. FKBP38 is the direct negative regulato...

We first cloned Xenopus Rheb, which is generally believed as the upstream positive regulator of TOR, then created dominant negative form of Rheb (dn-Rheb), and also designed antisense morpholino oligomers of Rheb (Rheb-MO). Gain-of-functional experiment of TOR signal by microinjection of Rheb mRNA into blastomeres led the posterior defects for the embryos. FKBP38 is the direct negative regulato...

Neuronal activity results in long term cellular changes that underlie normal brain development and synaptic plasticity. To examine the molecular basis of activity-dependent plasticity, we have used differential cloning techniques to identify genes that are rapidly induced in brain neurons by synaptic activity. Here we describe an inducible novel member of the Ras family of small GTP-binding pro...

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, ...

The mammalian target of rapamycin (mTOR) represents a critical signaling crossroad where pathways commonly disrupted in cancer converge. We report here that Rheb GTPase, the upstream activator of the mTOR complex 1 (mTORC1) is amplified in human prostate cancers. We demonstrate that Rheb overexpression promotes hyperplasia and a low-grade neoplastic phenotype in the mouse prostate while eliciti...