The mammalian target of rapamycin (mTOR) has a central role in the regulation of cell growth. mTOR receives input from multiple signaling pathways, including growth factors and nutrients, to stimulate protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase and eukaryote initiation factor 4E binding protein 1. High levels of dysregulated mTOR activity are associated with several hamartoma syndromes, including tuberous sclerosis complex, the PTEN-related hamartoma syndromes and Peutz-Jeghers syndrome. These disorders are all caused by mutations in tumor-suppressor genes that negatively regulate mTOR. Here we discuss the emerging evidence for a functional relationship between the mTOR signaling pathway and several genetic diseases, and we present evidence supporting a model in which dysregulation of mTOR may be a common molecular basis, not only for hamartoma syndromes, but also for other cellular hypertrophic disorders.

Tuberous sclerosis complex (TSC) and Peutz-Jeghers syndrome (PJS) are dominantly inherited benign tumor syndromes that share striking histopathological similarities. Here we show that LKB1, the gene mutated in PJS, acts as a tumor suppressor by activating TSC2, the gene mutated in TSC. Like TSC2, LKB1 inhibits the phosphorylation of the key translational regulators S6K and 4EBP1. Furthermore, we show that LKB1 activates TSC2 through the AMP-dependent protein kinase (AMPK), indicating that LKB1 plays a role in cell growth regulation in response to cellular energy levels. Our results suggest that PJS and other benign tumor syndromes could be caused by dysregulation of the TSC2/mTOR pathway.Supplemental material is available at http://www.genesdev.org.Received February 29, 2004; revised version accepted April 27, 2004. Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome characterized by the development of benign tumors termed hamartomas in a wide range of tissues. The majority of TSC cases are caused by mutation in either the tsc1 or tsc2 tumor suppressor genes (Young and Povey 1998). The proteins TSC1 and TSC2 form a functional complex and inhibit cell growth by negatively regulating the mammalian target of rapamycin (mTOR; Kwiatkowski 2003). mTOR controls cell growth by phosphorylating key substrates such as p70 ribosomal S6 kinase 1 (S6K) and eukaryote initiation factor 4E binding protein 1 (4EBP1; Jacinto and Hall 2003). Peutz-Jeghers syndrome (PJS), another dominantly inherited genetic disorder, is characterized by the formation of gastrointestinal hamartomas that happen to be histologically similar to those observed in TSC patients (Devroede et al. 1988). PJS is associated with mutations in the lkb1 tumor suppressor gene, which codes for a serine/threonine kinase. Although extensive work has been performed on the molecular pathogenesis of TSC, the molecular mechanism of LKB1 as a tumor suppressor has remained elusive.Recent studies from several laboratories have demonstrated that LKB1 phosphorylates and activates AMPK, representing the first convincing physiological target of LKB1 (Hawley et al. 2003;Hong et al. 2003;Woods et al. 2003, Shaw et al. 2004. AMPK is a multimeric protein, and its kinase activity is enhanced by both phosphorylation and high intracellular AMP levels. The amount of AMP in the cell is inversely proportional to the amount of ATP, and high levels of AMP are present under low energy conditions. Under such conditions, AMPK is activated and phosphorylates numerous substrates to suppress anabolism and enhance catabolism, thereby regulating cellular energy homeostasis (Hardie and Hawley 2001). LKB1 potentiates the effect of AMP on AMPK by phosphorylating AMPK on Thr 172, a residue found in the AMPK activation loop.Previous studies in our laboratory have demonstrated that activated AMPK phosphorylates and activates the TSC2 tumor suppressor protein (Inoki et al. 2003). This AMPK-dependent regulation of TSC2 is especially important for cellular energy response because cells e...

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The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays an essential role in cell growth control. mTOR stimulates cell growth by phosphorylating p70 ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1 (4EBP1). The mTOR pathway is regulated by a wide variety of cellular signals, including mitogenic growth factors, nutrients, cellular energy levels, and stress conditions. Recent studies have proposed several mechanisms to explain how mTOR is regulated by growth factors and cellular energy levels. However, little is known as to how mTOR is regulated by stress conditions. We observed that two stress-induced proteins, RTP801/Redd1 and RTP801L/Redd2, potently inhibit signaling through mTOR. Our data support that RTP801 and RTP801L work downstream of AKT and upstream of TSC2 to inhibit mTOR functions. These results add a new dimension to mTOR pathway regulation and provide a possible molecular mechanism of how cellular stress conditions may regulate mTOR function.A fundamental question in cell biology is how various extracellular cues can cause changes in translational output and hence the growth of the cell. The mammalian target of rapamycin (mTOR) 1 is a key regulator of translation that acts to stimulate protein synthesis by phosphorylating the ribosomal translation regulators p70 ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1 (4EBP1) (reviewed in Refs. 1-4). mTOR is known to receive inputs from multiple signaling pathways and responds by increasing or decreasing protein synthesis appropriately. A prominent example of this phenomenon is how mTOR is stimulated by growth factors and the availability of nutrients, while it is inhibited by conditions such as low ATP levels, the absence of nutrients, or cellular stressors such as DNA damage or hypoxia. Regulation of protein synthesis by mTOR is responsible for controlling cell size and proliferation, and it has recently been shown that mTOR may also regulate other cellular processes such as cytoskeletal organization, mRNA turnover, transcription, and autophagy (1). Dysregulation of the mTOR pathway in vivo is associated with several inherited human syndromes, including tuberous sclerosis complex (TSC), the PTEN hamartoma tumor syndromes, and Peutz-Jeghers Syndrome (5, 6).The tuberous sclerosis complex gene products, TSC1 and TSC2, are negative regulators of the mTOR signaling network (7). TSC1 and TSC2 form a complex in the cell, and the integrity of the TSC1/2 complex is essential for either protein to function. Cells or tissues lacking TSC1 or TSC2 display high levels of mTOR activation as measured by the activation status of S6K and 4EBP1, indicating that the TSC1/2 complex negatively regulates mTOR function (8 -11). This inhibition occurs via the GAP (GTPase-activating protein) domain of TSC2. The target of the GAP activity of TSC2 is the small G protein Rheb, a potent positive upstream regulator of mTOR (12)(13)(14). Several studies have found that TSC2 stimulates GTP hydrolysis an...

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