Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2015 Jul 6.
Published in final edited form as: J Cell Physiol. 2013 Aug;228(8):1658–1664. doi: 10.1002/jcp.24351

mTOR Signaling for Biological Control and Cancer

Anya Alayev 1, Marina K Holz 1,2,3,*
PMCID: PMC4491917  NIHMSID: NIHMS548956  PMID: 23460185

Abstract

Mammalian target of rapamycin (mTOR) is a major intersection that connects signals from the extracellular milieu to corresponding changes in intracellular processes. When abnormally regulated, the mTOR signaling pathway is implicated in a wide spectrum of cancers, neurological diseases, and proliferative disorders. Therefore, pharmacological agents that restore the regulatory balance of the mTOR pathway could be beneficial for a great number of diseases. This review summarizes current understanding of mTOR signaling and some unanswered questions in the field. We describe the composition of the mTOR complexes, upstream signals that activate mTOR, and physiological processes that mTOR regulates. We also discuss the role of mTOR and its downstream effectors in cancer, obesity and diabetes, and autism.

The mammalian target of rapamycin (mTOR, also known as the mechanistic target of rapamycin) is a 289 kDa serine/threonine kinase that belongs to the family of phosphatidylinositol 3-kinase-related kinases (PIKK). It was discovered as a target for a molecule called rapamycin, an anti-fungal macrolide produced by the bacterium Streptomyces hygroscopicus (Vezina et al., 1975). Rapamycin binds to FK506-binding protein of 12 kDa (FKBP12) and inhibits mTOR by interacting with the FKBP12-rapamycin binding domain (FRB) of mTOR (Brown et al., 1994; Sabatini et al., 1994). Rapamycin was found to strongly inhibit cell cycle progression, implicating mTOR in regulation of cell growth and proliferation (Brown et al., 1994; Sabers et al., 1995). Since then, mTOR has been a primary focus of many research groups that discovered a variety of other critical cellular mTOR-regulated processes such as metabolism, survival, protein and lipid synthesis, and autophagy. The best characterized targets of mTOR are the eukaryotic initiation factor 4E binding protein 1 (4E-BP1) and the p70 ribosomal S6 kinase 1 (S6K1). The mTOR pathway is dysregulated in a number of human diseases such as cancers, proliferative diseases, autism spectrum disorders, and type 2 diabetes. mTOR interacts with other proteins to form two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2; Laplante and Sabatini, 2009). These complexes differ from each other in their protein composition as well as in their sensitivity to rapamycin, with mTORC1 being acutely rapamycin-sensitive and mTORC2 being rapamycin-insensitive.

mTORC1

mTORC1 components and their function

mTORC1 is regulated by different signals including growth factors, genotoxic stress, oxygen levels, amino acids, and energy status of the cell; it integrates these signals to regulate anabolic (protein and lipid synthesis, and nutrient storage) and catabolic (autophagy and use of stored energy) processes of the cell (Sengupta et al., 2010). mTORC1 is largely sensitive to inhibition by rapamycin, which is used to treat solid tumors, organ rejection after transplantation, coronary restenosis, and rheumatoid arthritis (Kreis et al., 2000; Koehl et al., 2004; Molina et al., 2011; Kohno et al., 2013).

mTORC1 is composed of five proteins: mTOR, regulatory-associated protein of mTOR (Raptor), proline-rich AKT substrate 40 kDa (PRAS40), mammalian lethal with Sec13 protein 8 (mLST8, also known as GβL), and DEP-domain-containing mTOR interacting protein (DEPTOR). Raptor is a 150 kDa protein that binds to mTOR, allowing it to bind and phosphorylate downstream proteins such as the S6Ks, 4EBPs, and STAT3 (Hara et al., 2002; Kim et al., 2002; Schalm and Blenis, 2002; Schalm et al., 2003; Gulati et al., 2009). Additionally, raptor is important for sensing amino acids and regulating the subcellular localization of mTORC1 (Sancak et al., 2008). The role of mLST8 in mTORC1 function is not clear, as deletion of this protein does not affect mTORC1 activity (Guertin et al., 2006).

PRAS40 and DEPTOR are negative regulators of mTORC1. When mTORC1 is activated, it is able to directly phosphorylate PRAS40 and DEPTOR, which reduces their physical interaction with mTORC1 (Oshiro et al., 2007; Peterson et al., 2009). PRAS40 binds to raptor, but upon stimulation with insulin dissociates from mTORC1, thereby relieving its negative effect (Sancak et al., 2007; Wang et al., 2008). DEPTOR is highly overexpressed in multiple myelomas, where it maintains cell survival through high phosphoinositide 3-kinase (PI3K) and AKT activity levels (Peterson et al., 2009).

mTORC1 regulation

All signaling pathways that activate mTORC1 (with the exception of amino acids) act through the tuberous sclerosis complex (TSC) proteins TSC1 and TSC2. Mutation or loss of heterozygosity of TSC1/2 cause tuberous sclerosis, a disease characterized by numerous benign tumors. TSC1/2 complex negatively regulates mTORC1 by converting small Ras-related GTPase (Rheb) into its inactive GDT-bound state (Tee et al., 2002). When Rheb is in its GTP-bound form, it directly interacts with and activates mTORC1, but the exact mechanism by which Rheb activates mTOR is unclear. When TSC is phosphorylated, the repressive function is removed so that GTP-bound Rheb can activate mTORC1 (Inoki et al., 2003; Tee et al., 2003).

Upstream signals that regulate mTORC1

Growth factors

When nutrients are high, levels of growth factors such as insulin and IGF-1 are plentiful and promote anabolic processes of the cell through mTORC1. When insulin binds to its tyrosine kinase receptor, insulin substrate receptor 1 (IRS1) is recruited to the plasma membrane-bound receptor and activates PI3K, which produces phosphoinositol (3,4,5)-triphosphate (PIP3) and recruits Akt to the membrane for full activation. Akt in turn phosphorylates and inactivates TSC2, a negative regulator of mTORC1 (Potter et al., 2002; Roux et al., 2004); however, it is unclear how phosphorylation of TSC2 leads to its inactivation. Growth factors also activate mTORC1 through the Ras signaling pathway effectors ERK1/2 and p90 ribosomal S6 kinase 1 (RSK1; Roux et al., 2004; Ma et al., 2005). Downstream of mTORC1, AKT specifically phosphorylates and inhibits 4E-BP1, a translational repressor, but is sometimes dispensable for S6K1 phosphorylation and activation (Gingras et al., 1998; Dufner et al., 1999). Growth factors can also activate mTORC1 in a TSC-independent manner through phospholipase-D (PLD)-dependent accumulation of PA (phosphatidic acid), which directly binds to the FRB domain of mTORC1 and activates its downstream signaling (Fang et al., 2003). However, PA alone is not sufficient to activate mTORC1, and it is not entirely clear whether this process is truly TSC-independent (Sun et al., 2008). Loss of growth factor signaling represses mTORC1 activity, which leads to lower energy and nutrient consumption and an increase in the lifespan of an organism. Conversely, hyperactivation of growth factor signaling or loss of TSC1 or TSC2 leads to inappropriate activation of mTORC1, causing various pathologies, including cancer, cardiac hypertrophy, and neuronal dysfunction.

Energy levels

mTORC1 also senses energy status of the cell; specifically when intracellular energy levels are high, mTORC1 is activated and when energy levels are low, mTORC1 is inactivated. AMP-activated protein kinase (AMPK) relays the intracellular energy status of the cell to mTORC1. When energy is low, AMPK phosphorylates TSC2, which increases its affinity for the inactive, GDP-bound Rheb, which in turn blocks mTORC1 activity (Corradetti et al., 2004; Shaw et al., 2004). AMPK can also block mTORC1 activity directly by phosphorylating raptor (Gwinn et al., 2008).

Oxygen levels

Hypoxia, or low oxygen levels, is sensed by low ATP levels, which blocks signaling to mTORC1 through AMPK activation of TSC as well as inhibition and inactivation of raptor (Liu et al., 2006; Gwinn et al., 2008). Hypoxia also leads to activation of transcriptional regulation of DNA damage response 1 (REDD1), which releases TSC2 from interacting with 14-3-3 proteins. This allows TSC1/2 complex to inhibit mTORC1 (Brugarolas et al., 2004; DeYoung et al., 2008). Recent studies have called into question whether REDD1 directly binds to 14-3-3 (Vega-Rubin-de-Celis et al., 2010). Additionally, tumor suppressor promyelocytic leukemia (PML) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) disrupt mTORC1 interaction with Rheb, its positive regulator, and block mTORC1 signaling (Bernardi et al., 2006; Li et al., 2007).

Amino acids

Amino acids, particularly leucine, strongly activate mTORC1 and are transported into the cell in a glutamine-dependent fashion (Nicklin et al., 2009). Withdrawal of amino acids causes dephosphorylation of S6K1 and 4E-BP1, while addition of amino acids to the media restores their phosphorylation (Hara et al., 1998). This activation of mTORC1 by amino acids is TSC-independent because amino acid signaling to mTOR occurs even in cells that lack TSC2 (Smith et al., 2005). Moreover, overexpression of Rheb activates mTORC1 even in the absence of amino acids (Long et al., 2005). Rag proteins bind to Raptor in an amino acid-sensitive manner and activate mTORC1 by localizing it to the cytosolic side of the lysosomal membranes, where it interacts with Rheb (Smith et al., 2005; Sancak et al., 2010).

Genotoxic stress

Genotoxic stress reduces mTORC1 activity. When DNA is damaged, p53 is activated, which in turn activates AMPK, leading to activation of TSC2 and inhibiting mTORC1 activity (Budanov and Karin, 2008). However, it is unclear how p53 activates AMPK. p53 also negatively regulates mTORC1 by activating two negative regulators of the pathway: TSC2 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which opposes the activity of PI3K (Feng et al., 2005).

Inflammation

Inflammation causes activation of pro-inflammatory cytokines such as TNFα, which activates IκB kinase-β (IKKβ). IKKβ physically interacts and inactivates TSC1, thereby activating mTORC1 (Lee et al., 2007). This pathway is thought to be important in tumor angiogenesis and insulin resistance.

mTORC1 inhibitors

Rapamycin is a specific inhibitor of mTORC1. It remains unknown how rapamycin blocks mTORC1 activity as it does not affect complex formation or autophosphorylation of mTORC1; however, it may affect the affinity of raptor interaction with the complex (Kim et al., 2002). Recent reports suggest that prolonged treatment with rapamycin causes disintegration of mTORC1 (Yip et al., 2010). It also remains unclear why some mTORC1 downstream targets are rapamycin-sensitive, while others are rapamycin-insensitive (Peterson et al., 2000; Kudchodkar et al., 2004; Thoreen et al., 2009). Although rapamycin primarily inhibits mTORC1 and not mTORC2, prolonged treatment of rapamycin can also inhibit mTORC2 by blocking its assembly and causing disintegration of mTORC2 (Sarbassov et al., 2006; Barilli et al., 2008; Rosner and Hengstschlager, 2008; Hong et al., 2013).

Downstream pathways of mTORC1

mTORC1 regulates a number of downstream processes including protein synthesis, lipid synthesis, cholesterol synthesis, mitochondrial metabolism, and autophagy.

Protein synthesis

mTORC1 activates protein synthesis by phosphorylating 4E-BP1 and S6K1, the two most studied downstream targets of mTORC1. S6K1 regulates cell size, protein translation, and cell proliferation (Holz, 2012). Activation of S6K1 by mTORC1 leads to increased protein synthesis through regulation of several substrates: S6K1 aly-REF-like target (SKAR), programmed cell death 4 (PDCD4), eukaryotic initiation factor 4B (eIF4B), eukaryotic elongation factor 2 kinase (eEF2K), and ribosomal protein S6 (Wang et al., 2001; Raught et al., 2004; Richardson et al., 2004). eEF2K negatively regulates translation elongation by repressing eukaryotic elongation factor 2 (eEF2). S6K1 directly phosphorylates eEF2K, relieving its negative regulatory effect on protein synthesis. eIF4A is an RNA helicase that unwinds 50UTR secondary structures that may impede ribosome movement. S6K1 phosphorylates PDCD4, an inhibitor of eIF4A, leading to its degradation, thereby promoting efficient translation (Dorrello et al., 2006). eIF4B is an accessory factor that activates eIF4A. Phosphorylation by S6K1 increases the recruitment of eIF4B into the translation initiation complex (Raught et al., 2004; Holz et al., 2005). Phosphorylation of SKAR by S6K1 promotes translation efficiency of spliced mRNAs (Ma et al., 2008).

Transgenic mice with mutations in S6K1 or 4E-BPs show severe metabolic changes. S6K1-null mice are hypoinsulinemic but are also hypersensitive to insulin signaling. These mice do not accumulate fat as they have increased lipolysis of triglycerides from stored adipose tissue and have an increased lifespan (Pende et al., 2000;Um et al., 2004; Selman et al., 2009). In contrast, mice deficient in both 4E-BP1 and 4E-BP2 exhibit a completely opposite phenotype of an increase in adipose tissue (Le Bacquer et al., 2007).

S6, a component of the 40S ribosomal subunit, is phosphorylated by S6K1, which under growth-promoting conditions causes increased rates of protein synthesis. However, when a nonphosphorylatable version of S6 is expressed, cells also exhibit high rates of protein synthesis, hence the function and mechanism of S6 in protein synthesis remains unclear (Ruvinsky et al., 2005). S6 is also phosphorylated by RSK in an mTOR-independent manner (Roux et al., 2007).

4E-BP1 represses eIF4E, a rate limiting protein of cap-dependent translation. When mTORC1 phosphorylates 4E-BP1, it disassociates from eIF4E and allows it to recruit protein translation machinery to the 50 cap of eukaryotic mRNAs (Gingras et al., 2001), leading to activation of cap-dependent translation. 4E-BP1 is phosphorylated by mTOR on four sites, two of which are acutely rapamycin-sensitive. However, rapamycin inhibition of 4E-BP1 is not as potent and permanent as that of S6K1 (Choo et al., 2008). Recent studies have shown that high-dose treatment of rapamycin causes apoptosis in human cancer cell lines, which is associated with inhibition of 4E-BP1 phosphorylation and dissociation of raptor from mTORC1 (Yellen et al., 2011).

Metabolic pathways

mTORC1 regulates metabolic pathways on transcriptional, translational, and posttranslational levels. When rapamycin inhibits mTORC1 in lymphoma cells, it induces changes in the levels of mRNAs encoding metabolic enzymes involved in glycolysis, amino acid, sterol, lipid, and nucleotide metabolism (Peng et al., 2002). mTORC1 activates SREBP-1, transcription factor belonging to the sterol regulatory element binding proteins (SREBPs) family, as inhibition of mTORC1 by rapamycin blocks expression of SREBP target genes (Porstmann et al., 2008). SREBP-1 is found in an inactive state on the Endoplasmic Reticulum and is escorted to the Golgi in response to low sterol, insulin, or fatty acid levels, where it is processed into the active form. Once active, SREBP-1 translocates to the nucleus where it binds to promoters of genes containing sterol regulatory elements and Enhancer Box sequences. mTORC1 is thought to activate SREBP-1 through S6K1 by promoting posttranslational processing (Duvel et al., 2010).

Lipid and cholesterol synthesis

mTORC1 promotes lipid and cholesterol synthesis by activation of SREBP-1 and peroxisome proliferator-activator-γ (PPARγ; Kim and Chen, 2004; Porstmann et al., 2008). Rapamycin treatment reduces PPARγ expression as well as phosphorylation of lipin-1, a phosphatidic acid (PA) phosphatase that is involved in glycerolipid synthesis. The exact mechanism of SREBP1 activation by mTORC1, as well as the importance of lipin-1 phosphorylation on lipid synthesis, remain unclear.

Mitochondrial metabolism

mTORC1 regulates mitochondrial number and function, because inhibition of mTORC1 by rapamycin lowers mitochondrial membrane potential, oxygen consumption, and cellular ATP, while hyperactivation of mTORC1 increases mitochondrial DNA copy number (Schieke et al., 2006). Additionally, studies in mice found that lack of raptor reduces expression of genes involved in mitochondrial biogenesis (Bentzinger et al., 2008).

Autophagy

Autophagy is a process through which cells are able to create and use intracellular energy by degrading cytoplasmic proteins and organelles in lysosomes during times of nutritional deprivation. The intracellular components targeted for degradation are sequestered inside autophagosomes and are degraded through fusion with lysosomes. Autophagy is inhibited in the presence of nutrients and growth factors and is upregulated during starvation, growth factor withdrawal, oxidative stress, and infection (Codogno and Meijer, 2005). This process is also important for general cellular housekeeping. Autophagy is regulated by mTORC1, and correspondingly, mTOR was found to localize to the lysosomal surface (Sancak et al., 2010). When mTORC1 is activated under high nutrient conditions, autophagy is inhibited; conversely, mTORC1 inhibition stimulates autophagy, which leads to the release of amino acids through protein degradation, which in turn activates mTORC1. Autophagy mediator ULK forms a complex with Atg13 and FIP200, promoting autophagy induction. mTORC1 phosphorylates ULK and Atg13, but the role of this phosphorylation is unclear (Ganley et al., 2009). While autophagy is negatively regulated by mTORC1, it remains unclear why this process could be either activated or inhibited by rapamycin, with S6K1 having a positive role in autophagy induction (Armour et al., 2009).

Negative feedback loops

mTORC1 activation by growth factors leads to activation of several negative feedback loops, which modulate growth factor signaling pathway activation. Akt signals via TSC1/2 to activate mTORC1 and its downstream target S6K1. S6K1, in turn, reduces IRS1 activity by phosphorylating it, preventing its binding to the insulin receptor and causing its subsequent degradation (Harrington et al., 2004; Shah and Hunter, 2006). S6K1 interacts with IRS1 through raptor, phosphorylating and inactivating it (Tzatsos, 2009). S6K1 similarly suppresses activity of platelet-derived growth factor receptor (PDFR; Zhang et al., 2003). S6K1 also leads to mTORC1 phosphorylation on Ser2448 (Holz and Blenis, 2005). While the role of this event is not understood, it may act to modulate negative inhibition within the “repressor domain” of mTOR (Sekulic et al., 2000). Growth factor receptor-bound protein 10 (Grb10) is a putative tumor suppressor that is frequently downregulated in a number of cancers. Recently, it has been characterized as a substrate of mTORC1, with mTORC1 stabilizing Grb10 and inhibiting PI3K (Hsu et al., 2011; Yu et al., 2011). DEPTOR, the negative regulator of mTORC1, was found to promote adipogenesis by blocking the mTORC1-mediated negative feedback inhibition of insulin signaling (Laplante et al., 2012).

mTORC2

mTORC2 components and their function

mTORC2 is comprised of six proteins: mTOR, rapamycin-insensitive companion of mTOR (Rictor), mammalian stress-activated protein kinase interacting protein (mSIN1), protein observed with rictor-1 (Protor-1), mLST8, and DEPTOR. Very little is known about mTORC2, the function of its components, the upstream signals it integrates and its downstream targets. Deletion of mTORC2 protein components in mice causes early embryonic lethality phenotype (Guertin et al., 2006; Shiota et al., 2006), which makes it challenging to study its function, compounded by the fact that there are no known specific inhibitors of mTORC2.

mTORC2 is characterized by association with rictor, a binding partner for mTOR, whose interaction is mutually exclusive with that of raptor, a binding partner of mTORC1 (Jacinto et al., 2004; Sarbassov et al., 2004). Rictor is essential for mTORC2 catalytic activity and may have a function in recruitment of other substrates to mTORC2 (Sarbassov et al., 2004). Rictor also binds to mSIN1 and these proteins help to stabilize each other (Frias et al., 2006; Jacinto et al., 2006); however, other functions of mSIN1 are unknown.

Protor-1 (aka PRR5) specifically binds to rictor; however, this interaction is independent of mTOR and is not required for mTORC2 activation (Thedieck et al., 2007; Woo et al., 2007). Thus the function of protor-1 or the significance of its binding to rictor is unknown. mLST8 is required for mTORC2 activity, as knockdown of mLST8 severely reduces the stability and activity of mTORC2 (Guertin et al., 2006). DEPTOR negatively regulates mTORC2 through the FRAP-ATM-TTRAP (FAT) domain of mTORC2 and is the only characterized endogenous inhibitor of mTORC2 (Peterson et al., 2009).

When active, mTORC2 is phosphorylated on Ser2481 (Copp et al., 2009) and is important for cell survival, metabolism, proliferation, and cytoskeletal organization. mTORC2 phosphorylates Protein Kinase Cα (PKC), which regulates cell proliferation, differentiation, apoptosis, and telomerase activities and is constitutively active in hematopoetic cancers, where it promotes cell proliferation and survival (Ikenoue et al., 2008; Yamada et al., 2010; Zhang et al., 2012). Knockdown of mTORC2 components disrupts cell morphology and actin polymerization (Loewith et al., 2002; Jacinto et al., 2004). While mTORC2 is rapamycin-insensitive, studies suggest that it can be sensitive to rapamycin in some cancer cell lines, using Ser2481 phosphorylation as a read-out (Copp et al., 2009).

The serine/threonine kinase AKT is activated downstream of PI3K signaling. Akt is important for cell survival, metabolism, and proliferation, and its full activation requires phosphorylation at Ser308 by PDK1 and at Ser473 by mTORC2 (Sarbassov et al., 2005). The importance of mTORC2 in Akt activation is also demonstrated by the fact that deletion of rictor, mLST8, and SIN1 components of mTORC2 blocks AKT phosphorylation at Ser473 (Guertin et al., 2006; Jacinto et al., 2006; Shiota et al., 2006). Research suggests that TSC1 and TSC2 physically interact with mTORC2 and positively regulate its activity, as cells lacking TSC1/2 have impaired phosphorylation of AKT by mTORC2 (Huang et al., 2008).

Another target of mTORC2 is serum- and glucocorticoid-induced protein kinase 1 (SGK1). SGK1 is activated by growth factors and phosphorylates proteins involved in growth and ion transport and is regulated by mTORC2 through phosphorylation at Ser422 (Garcia-Martinez and Alessi, 2008). Together, these data seem to indicate that growth factors might be one of the upstream signals that regulate mTORC2.

mTORC1 and mTORC2 regulation of each other

Within the mTOR signaling network, there exist unexplained questions regarding the nature of the relationship and the extent of the interplay between mTORC1 and mTORC2. mTORC1 and mTORC2 contain raptor or rictor, respectively, and these two proteins are mutually exclusive in their association with mTOR. Additionally, we know that mTORC1 is largely sensitive to rapamycin treatment, while mTORC2 is acutely rapamycin-insensitive. However, studies have shown that prolonged treatment of rapamycin does inhibit mTORC2 assembly and function (Guertin et al., 2006; Sarbassov et al., 2006). Recent studies suggest that low doses of rapamycin affect mTORC1 signaling, while higher doses primarily affect mTORC2 (Chen et al., 2010). Additionally, S6K1 was found to phosphorylate rictor on Thr1135 in a rapamycin-sensitive manner, suggesting that there exists important cross-talk between mTORC1 and mTORC2 complexes (Julien et al., 2010). More studies are needed to further understand this relationship and its implications for regulation of downstream targets.

Is there another mTOR complex?

Studies of 4E-BP1 phosphorylation utilizing the ATP-competitive mTOR inhibitor Torin 1 revealed that while the inhibitory effects of this compound were greater than rapamycin treatment alone and similar to results obtained with raptor knock-down, there was no appreciable difference when Torin1 was used in cells lacking rictor (Thoreen et al., 2009). These data provide rationale for the possible existence of a distinct rapamycin-insensitive mTOR complex, which may contain raptor. Another piece of evidence for the existence of additional mTOR complexes comes from studies of 5′-terminal oligopyrimidine tract (5′ TOP), a feature of proteins involved with the translational machinery. Translation of the TOP mRNAs is regulated by the PI3K/mTOR pathway; however, the mechanism is still unclear. TOP mRNA synthesis was initially thought to be regulated by S6K1 but this mechanism was subsequently challenged by other groups, because activation of S6K1 did not relieve translational repression of TOP mRNAs (Tang et al., 2001), and S6K1/S6K2 double knockout mice were still able to translate TOP mRNA in a rapamycin-sensitive manner (Pende et al., 2004). Rapamycin treatment has a broad range of effects on TOP mRNA translation, and knockdown of either raptor or rictor has only a slight effect (Patursky-Polischuk et al., 2009; Conn and Qian, 2011). Together, these data support the hypothesis that there exists an additional mTOR complex, a putative “mTORC3.” This complex might have additional binding proteins that regulate its specificity towards a potentially different set of downstream proteins.

mTOR in cancer and disease

mTOR is an important mediator of cancer progression and this pathway is frequently deregulated during tumor formation through the loss of PTEN, activation of PI3K, or overexpression of AKT (Depowski et al., 2001; Kirkegaard et al., 2005). TSC1/2 is a tumor suppressor complex, mutations in which lead to tuberous sclerosis (TSC), a syndrome characterized by benign tumors composed of large cells some of which become malignant, or lymphangioleiomyomatosis (LAM), a lung disease characterized by abnormal proliferation of smooth muscle cells. Since TSC inhibition leads to hyperactivation of mTOR, drugs that inhibit the mTOR pathway would benefit TSC and LAM patients. Inactivation of the tumor suppressor PTEN leads to hyperactivation of AKT and mTOR, and PTEN is often mutated in human cancers (Neshat et al., 2001). These patients would benefit from rapamycin-like inhibitors of mTORC1; however inhibition of mTORC1 using rapamycin also relieves the S6K1-mediated negative feedback loop, upregulating PI3K/AKT signaling and promoting cell growth, survival, and migration. Under homeostatic conditions, this negative feedback loop may be a powerful way of impeding oncogenesis following growth factor stimulation. This may explain why rapamycin treatment is not an effective monotherapy in cancer patients. Thus, current therapeutic strategies seek inhibition of both the mTOR and PI3K/AKT pathways.

Amplification of chromosomal region containing the gene for S6K1 occurs frequently in breast cancer, which is associated with poor prognosis in patients (Perez-Tenorio et al., 2011). It has been shown that S6K1 regulates estrogen receptorα (ERα), and allows cells to proliferate under low-serum conditions (Yamnik et al., 2009). S6K1 specifically phosphorylates ERα on Ser167, contributing to endocrine therapy resistance in breast cancer (Yamnik and Holz, 2010). Estrogen also activates S6K1 expression through ERα, while S6K1 in turn phosphorylates and activates ERα, creating a positive regulatory loop (Holz, 2012; Maruani et al., 2012). This positive co-regulatory loop between the mTORC1/S6K1 and ERα signaling explains the success of the combination therapy targeting these two pathways in hormone-positive breast cancer (Baselga et al., 2009; Baselga et al., 2012).

Type 2 diabetes is caused by chronic overfeeding and insulin resistance which leads to accumulation of high levels of glucose and amino acids in the blood. mTORC1 appears to be involved in the pathogenesis of type 2 diabetes. Obese rats have high levels of mTOR and S6K1 and reduced IRS-1 expression, which is reverted by rapamycin treatment (Khamzina et al., 2005). Recent studies suggest that mTORC2 disruption also contributes to insulin resistance (Lamming et al., 2012; Ye et al., 2012).

Autism spectrum disorder (ASD) is characterized by impaired social and intellectual abilities and restricted, repetitive behavior, affecting about 1% of children. Mutations of various components of mTOR signaling pathway have been associated with ASD (Ehninger and Silva, 2011; Veenstra-VanderWeele and Blakely, 2012). Heterozygous mutation of TSC1 or TSC2 is associated with ASD and epilepsy, possibly because Tsc1 and Tsc2 are important for axon formation and growth (Choi et al., 2008). Mouse models heterozygous for Tsc2 mutations show memory and learning defects, and some of the behavioral defects are reversed upon treatment with rapamycin (Ehninger et al., 2008). Additionally, loss of PTEN also causes ASD, and mouse models also showed that rapamycin treatment can prevent as well as reverse some of the neuronal defects (Zhou et al., 2009). Aberrant synaptic translation has been implicated in the etiology of Fragile X Syndrome (FXS), the leading inherited cause of autism and intellectual disability. Removal of S6K1 in mice was found to correct the molecular, synaptic, and behavioral phenotypes in FXS (Bhattacharya et al., 2012). EIF4E, a downstream effector of mTOR, is also implicated in ASD, as this gene is deregulated in patients with ASD (Neves-Pereira et al., 2009).

Calorie restricting lifestyle extends lifespan and delays onset of age-related diseases in many different species from yeast to humans, and the mTOR signaling pathway is highly involved in the regulation of this process (Fontana et al., 2004, 2010; Harrison et al., 2009). Specifically, S6K1 and 4E-BP1 are implicated in modulation of aging because deletion of S6K1 in mice increases lifespan (Selman et al., 2009), while loss of 4E-BP in flies reduces lifespan (Zid et al., 2009). In mice, mTOR activity is increased in hematopoietic stem cells (HSC) of animals with conditional deletion of Tsc1 in the HSCs. Notably, rapamycin was able to increase lifespan and restore self-renewal of HSCs in old animals (Chen et al., 2009).

Future directions

Over the past 30 years much progress has been made in understanding the significance of mTOR as a central regulator of multiple cellular functions as well as its involvement in the pathogenesis and progression of several diseases. There are numerous current challenges ahead: to identify other cellular functions connected to the mTOR signaling pathway, to discover novel downstream components of the pathway, to elucidate how mTOR pathway dysregulation leads to some pathologies, and determine which mTOR pathway components are viable candidates for therapeutic intervention.

Acknowledgments

Contract grant sponsor: National Cancer Center (to A.A.).

Contract grant sponsor: NIH (to M.K.H.);

Contract grant number: CA151112.

Contract grant sponsor: Atol Charitable Trust (to M.K.H.).

Contract grant sponsor: Wendy Will Case Cancer Fund (to M.K.H.).

Contract grant sponsor: Yeshiva University.

Literature Cited

  1. Armour SM, Baur JA, Hsieh SN, Land-Bracha A, Thomas SM, Sinclair DA. Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging. 2009;1:515–528. doi: 10.18632/aging.100056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barilli A, Visigalli R, Sala R, Gazzola GC, Parolari A, Tremoli E, Bonomini S, Simon A, Closs EI, Dall’Asta V, Bussolati O. In human endothelial cells rapamycin causes mTORC2 inhibition and impairs cell viability and function. Cardiovasc Res. 2008;78:563–571. doi: 10.1093/cvr/cvn024. [DOI] [PubMed] [Google Scholar]
  3. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G, Steinseifer J, Molloy B, Tokaji E, Gardner H, Phillips P, Stumm M, Lane HA, Dixon JM, Jonat W, Rugo HS. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27:2630–2637. doi: 10.1200/JCO.2008.18.8391. [DOI] [PubMed] [Google Scholar]
  4. Baselga J, Campone M, Piccart M, Burris HA, III, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–529. doi: 10.1056/NEJMoa1109653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bentzinger CF, Romanino K, Cloetta D, Lin S, Mascarenhas JB, Oliveri F, Xia J, Casanova E, Costa CF, Brink M, Zorzato F, Hall MN, Ruegg MA. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 2008;8:411–424. doi: 10.1016/j.cmet.2008.10.002. [DOI] [PubMed] [Google Scholar]
  6. Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP. PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature. 2006;442:779–785. doi: 10.1038/nature05029. [DOI] [PubMed] [Google Scholar]
  7. Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, Murphy JP, Pierre P, Klann E. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron. 2012;76:325–337. doi: 10.1016/j.neuron.2012.07.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994;369:756–758. doi: 10.1038/369756a0. [DOI] [PubMed] [Google Scholar]
  9. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG., Jr Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004;18:2893–2904. doi: 10.1101/gad.1256804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 2008;134:451–460. doi: 10.1016/j.cell.2008.06.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chen C, Liu Y, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009;2:ra75. doi: 10.1126/scisignal.2000559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chen XG, Liu F, Song XF, Wang ZH, Dong ZQ, Hu ZQ, Lan RZ, Guan W, Zhou TG, Xu XM, Lei H, Ye ZQ, Peng EJ, Du LH, Zhuang QY. Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways. Mol Carcinog. 2010;49:603–610. doi: 10.1002/mc.20628. [DOI] [PubMed] [Google Scholar]
  13. Choi YJ, Di Nardo A, Kramvis I, Meikle L, Kwiatkowski DJ, Sahin M, He X. Tuberous sclerosis complex proteins control axon formation. Genes Dev. 2008;22:2485–2495. doi: 10.1101/gad.1685008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Choo AY, Yoon SO, Kim SG, Roux PP, Blenis J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci USA. 2008;105:17414–17419. doi: 10.1073/pnas.0809136105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Codogno P, Meijer AJ. Autophagy and signaling: Their role in cell survival and cell death. Cell Death Differ. 2005;12:1509–1518. doi: 10.1038/sj.cdd.4401751. [DOI] [PubMed] [Google Scholar]
  16. Conn CS, Qian SB. mTOR signaling in protein homeostasis: Less is more? Cell Cycle. 2011;10:1940–1947. doi: 10.4161/cc.10.12.15858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Copp J, Manning G, Hunter T. TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): Phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res. 2009;69:1821–1827. doi: 10.1158/0008-5472.CAN-08-3014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL. Regulation of the TSC pathway by LK B1: Evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev. 2004;18:1533–1538. doi: 10.1101/gad.1199104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Depowski PL, Rosenthal SI, Ross JS. Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol. 2001;14:672–676. doi: 10.1038/modpathol.3880371. [DOI] [PubMed] [Google Scholar]
  20. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 2008;22:239–251. doi: 10.1101/gad.1617608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M. S6K1- and beta TRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 2006;314:467–471. doi: 10.1126/science.1130276. [DOI] [PubMed] [Google Scholar]
  22. Dufner A, Andjelkovic M, Burgering BM, Hemmings BA, Thomas G. Protein kinase B localization and activation differentially affect S6 kinase 1 activity and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation. Mol Cell Biol. 1999;19:4525–4534. doi: 10.1128/mcb.19.6.4525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 2010;39:171–183. doi: 10.1016/j.molcel.2010.06.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ehninger D, Silva AJ. Rapamycin for treating Tuberous sclerosis and Autism spectrum disorders. Trends Mol Med. 2011;17:78–87. doi: 10.1016/j.molmed.2010.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, Ramesh V, Silva AJ. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med. 2008;14:843–848. doi: 10.1038/nm1788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Fang Y, Park IH, Wu AL, Du G, Huang P, Frohman MA, Walker SJ, Brown HA, Chen J. PLD1 regulates mTOR signaling and mediates Cdc42 activation of S6K1. Curr Biol. 2003;13:2037–2044. doi: 10.1016/j.cub.2003.11.021. [DOI] [PubMed] [Google Scholar]
  27. Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA. 2005;102:8204–8209. doi: 10.1073/pnas.0502857102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci USA. 2004;101:6659–6663. doi: 10.1073/pnas.0308291101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Fontana L, Partridge L, Longo VD. Extending healthy life span–from yeast to humans. Science. 2010;328:321–326. doi: 10.1126/science.1172539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol. 2006;16:1865–1870. doi: 10.1016/j.cub.2006.08.001. [DOI] [PubMed] [Google Scholar]
  31. Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009;284:12297–12305. doi: 10.1074/jbc.M900573200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1) Biochem J. 2008;416:375–385. doi: 10.1042/BJ20081668. [DOI] [PubMed] [Google Scholar]
  33. Gingras AC, Kennedy SG, O’Leary MA, Sonenberg N, Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev. 1998;12:502–513. doi: 10.1101/gad.12.4.502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev. 2001;15:807–826. doi: 10.1101/gad.887201. [DOI] [PubMed] [Google Scholar]
  35. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11:859–871. doi: 10.1016/j.devcel.2006.10.007. [DOI] [PubMed] [Google Scholar]
  36. Gulati N, Karsy M, Albert L, Murali R, Jhanwar-Uniyal M. Involvement of mTORC1 and mTORC2 in regulation of glioblastoma multiforme growth and motility. Int J Oncol. 2009;35:731–740. doi: 10.3892/ijo_00000386. [DOI] [PubMed] [Google Scholar]
  37. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:214–226. doi: 10.1016/j.molcel.2008.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem. 1998;273:14484–14494. doi: 10.1074/jbc.273.23.14484. [DOI] [PubMed] [Google Scholar]
  39. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110:177–189. doi: 10.1016/s0092-8674(02)00833-4. [DOI] [PubMed] [Google Scholar]
  40. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, Gout I, Downes CP, Lamb RF. The TSC 1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol. 2004;166:213–223. doi: 10.1083/jcb.200403069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–395. doi: 10.1038/nature08221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Holz MK. The role of S6K 1 in ER-positive breast cancer. Cell Cycle. 2012;11:3159–3165. doi: 10.4161/cc.21194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Holz MK, Blenis J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J Biol Chem. 2005;280:26089–26093. doi: 10.1074/jbc.M504045200. [DOI] [PubMed] [Google Scholar]
  44. Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123:569–580. doi: 10.1016/j.cell.2005.10.024. [DOI] [PubMed] [Google Scholar]
  45. Hong SM, Park CW, Cha HJ, Kwon JH, Yun YS, Lee NG, Kim DG, Nam HG, Choi KY. Rapamycin inhibits both motility through down-regulation of p-STAT3 (S727) by disrupting the mTORC2 assembly and peritoneal dissemination in sarcomatoid cholangiocarcinoma. Clin Exp Metastasis. 2013;30:177–187. doi: 10.1007/s10585-012-9526-9. [DOI] [PubMed] [Google Scholar]
  46. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, Marto JA, Sabatini DM. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332:1317–1322. doi: 10.1126/science.1199498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Huang J, Dibble CC, Matsuzaki M, Manning BD. The TSC1–TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol. 2008;28:4104–4115. doi: 10.1128/MCB.00289-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 2008;27:1919–1931. doi: 10.1038/emboj.2008.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17:1829–1834. doi: 10.1101/gad.1110003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6:1122–1128. doi: 10.1038/ncb1183. [DOI] [PubMed] [Google Scholar]
  51. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127:125–137. doi: 10.1016/j.cell.2006.08.033. [DOI] [PubMed] [Google Scholar]
  52. Julien LA, Carriere A, Moreau J, Roux PP. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol. 2010;30:908–921. doi: 10.1128/MCB.00601-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Khamzina L, Veilleux A, Bergeron S, Marette A. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: Possible involvement in obesity-linked insulin resistance. Endocrinology. 2005;146:1473–1481. doi: 10.1210/en.2004-0921. [DOI] [PubMed] [Google Scholar]
  54. Kim JE, Chen J. regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes. 2004;53:2748–2756. doi: 10.2337/diabetes.53.11.2748. [DOI] [PubMed] [Google Scholar]
  55. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110:163–175. doi: 10.1016/s0092-8674(02)00808-5. [DOI] [PubMed] [Google Scholar]
  56. Kirkegaard T, Witton CJ, McGlynn LM, Tovey SM, Dunne B, Lyon A, Bartlett JM. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol. 2005;207:139–146. doi: 10.1002/path.1829. [DOI] [PubMed] [Google Scholar]
  57. Koehl GE, Andrassy J, Guba M, Richter S, Kroemer A, Scherer MN, Steinbauer M, Graeb C, Schlitt HJ, Jauch KW, Geissler EK. Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. Transplantation. 2004;77:1319–1326. doi: 10.1097/00007890-200405150-00002. [DOI] [PubMed] [Google Scholar]
  58. Kohno J, Matsui Y, Yamasaki T, Shibasaki N, Kamba T, Yoshimura K, Sumiyoshi S, Mikami Y, Ogawa O. Role of mammalian target of rapamycin inhibitor in the treatment of metastatic epithelioid angiomyolipoma: A case report. Int J Urol. 2013 doi: 10.1111/iju.12095. [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
  59. Kreis H, Cisterne JM, Land W, Wramner L, Squifflet JP, Abramowicz D, Campistol JM, Morales JM, Grinyo JM, Mourad G, Berthoux FC, Brattstrom C, Lebranchu Y, Vialtel P. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation. 2000;69:1252–1260. doi: 10.1097/00007890-200004150-00009. [DOI] [PubMed] [Google Scholar]
  60. Kudchodkar SB, Yu Y, Maguire TG, Alwine JC. Human cytomegalovirus infection induces rapamycin-insensitive phosphorylation of downstream effectors of mTOR kinase. J Virol. 2004;78:11030–11039. doi: 10.1128/JVI.78.20.11030-11039.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012;335:1638–1643. doi: 10.1126/science.1215135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009;122:3589–3594. doi: 10.1242/jcs.051011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Laplante M, Horvat S, Festuccia WT, Birsoy K, Prevorsek Z, Efeyan A, Sabatini DM. DEPTOR cell-autonomously promotes adipogenesis, and its expression is associated with obesity. Cell Metab. 2012;16:202–212. doi: 10.1016/j.cmet.2012.07.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Le Bacquer O, Petroulakis E, Paglialunga S, Poulin F, Richard D, Cianflone K, Sonenberg N. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. J Clin Invest. 2007;117:387–396. doi: 10.1172/JCI29528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Lee DF, Kuo HP, Chen CT, Hsu JM, Chou CK, Wei Y, Sun HL, Li LY, Ping B, Huang WC, He X, Hung JY, Lai CC, Ding Q, Su JL, Yang JY, Sahin AA, Hortobagyi GN, Tsai FJ, Tsai CH, Hung MC. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell. 2007;130:440–455. doi: 10.1016/j.cell.2007.05.058. [DOI] [PubMed] [Google Scholar]
  66. Li Y, Wang Y, Kim E, Beemiller P, Wang CY, Swanson J, You M, Guan KL. Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb. J Biol Chem. 2007;282:35803–35813. doi: 10.1074/jbc.M705231200. [DOI] [PubMed] [Google Scholar]
  67. Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell. 2006;21:521–531. doi: 10.1016/j.molcel.2006.01.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P, Hall MN. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002;10:457–468. doi: 10.1016/s1097-2765(02)00636-6. [DOI] [PubMed] [Google Scholar]
  69. Long X, Ortiz-Vega S, Lin Y, Avruch J. Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J Biol Chem. 2005;280:23433–23436. doi: 10.1074/jbc.C500169200. [DOI] [PubMed] [Google Scholar]
  70. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. 2005;121:179–193. doi: 10.1016/j.cell.2005.02.031. [DOI] [PubMed] [Google Scholar]
  71. Ma XM, Yoon SO, Richardson CJ, Julich K, Blenis J. SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell. 2008;133:303–313. doi: 10.1016/j.cell.2008.02.031. [DOI] [PubMed] [Google Scholar]
  72. Maruani DM, Spiegel TN, Harris EN, Shachter AS, Unger HA, Herrero-Gonzalez S, Holz MK. Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation. Oncogene. 2012;31:5073–5080. doi: 10.1038/onc.2011.657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Molina AM, Ginsberg MS, Motzer RJ. Long-term response with everolimus for metastatic renal cell carcinoma refractory to sunitinib. Med Oncol. 2011;28:1527–1529. doi: 10.1007/s12032-010-9640-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA. 2001;98:10314–10319. doi: 10.1073/pnas.171076798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Neves-Pereira M, Muller B, Massie D, Williams JH, O’Brien PC, Hughes A, Shen SB, Clair DS, Miedzybrodzka Z. Deregulation of EIF4E: A novel mechanism for autism. J Med Genet. 2009;46:759–765. doi: 10.1136/jmg.2009.066852. [DOI] [PubMed] [Google Scholar]
  76. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 2009;136:521–534. doi: 10.1016/j.cell.2008.11.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A, Eguchi S, Miyamoto T, Hara K, Takehana K, Avruch J, Kikkawa U, Yonezawa K. The proline-rich Akt substrate of 40kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J Biol Chem. 2007;282:20329–20339. doi: 10.1074/jbc.M702636200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Patursky-Polischuk I, Stolovich-Rain M, Hausner-Hanochi M, Kasir J, Cybulski N, Avruch J, Ruegg MA, Hall MN, Meyuhas O. The TSC-mTOR pathway mediates translational activation ofTOP mRNAsby insulin largely in a raptor- or rictor-independent manner. Mol Cell Biol. 2009;29:640–649. doi: 10.1128/MCB.00980-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y, Klumperman J, Thorens B, Thomas G. Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature. 2000;408:994–997. doi: 10.1038/35050135. [DOI] [PubMed] [Google Scholar]
  80. Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, Fumagalli S, Kozma SC, Thomas G. S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5’-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol. 2004;24:3112–3124. doi: 10.1128/MCB.24.8.3112-3124.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Peng T, Golub TR, Sabatini DM. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol Cell Biol. 2002;22:5575–5584. doi: 10.1128/MCB.22.15.5575-5584.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Perez-Tenorio G, Karlsson E, Waltersson MA, Olsson B, Holmlund B, Nordenskjold B, Fornander T, Skoog L, Stal O. Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer. Breast Cancer Res Treat. 2011;128:713–723. doi: 10.1007/s10549-010-1058-x. [DOI] [PubMed] [Google Scholar]
  83. Peterson RT, Beal PA, Comb MJ, Schreiber SL. FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. J Biol Chem. 2000;275:7416–7423. doi: 10.1074/jbc.275.10.7416. [DOI] [PubMed] [Google Scholar]
  84. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137:873–886. doi: 10.1016/j.cell.2009.03.046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008;8:224–236. doi: 10.1016/j.cmet.2008.07.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol. 2002;4:658–665. doi: 10.1038/ncb840. [DOI] [PubMed] [Google Scholar]
  87. Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD, Sonenberg N, Hershey JW. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 2004;23:1761–1769. doi: 10.1038/sj.emboj.7600193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Richardson CJ, Broenstrup M, Fingar DC, Julich K, Ballif BA, Gygi S, Blenis J. SKAR is a specific target of S6 kinase 1 in cell growth control. Curr Biol. 2004;14:1540–1549. doi: 10.1016/j.cub.2004.08.061. [DOI] [PubMed] [Google Scholar]
  89. Rosner M, Hengstschlager M. Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTOR C2: Rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. Hum Mol Genet. 2008;17:2934–2948. doi: 10.1093/hmg/ddn192. [DOI] [PubMed] [Google Scholar]
  90. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA. 2004;101:13489–13494. doi: 10.1073/pnas.0405659101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem. 2007;282:14056–14064. doi: 10.1074/jbc.M700906200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Ruvinsky I, Sharon N, Lerer T, Cohen H, Stolovich-Rain M, Nir T, Dor Y, Zisman P, Meyuhas O. Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev. 2005;19:2199–2211. doi: 10.1101/gad.351605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAF T1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell. 1994;78:35–43. doi: 10.1016/0092-8674(94)90570-3. [DOI] [PubMed] [Google Scholar]
  94. Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem. 1995;270:815–822. doi: 10.1074/jbc.270.2.815. [DOI] [PubMed] [Google Scholar]
  95. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25:903–915. doi: 10.1016/j.molcel.2007.03.003. [DOI] [PubMed] [Google Scholar]
  96. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008;320:1496–1501. doi: 10.1126/science.1157535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010;141:290–303. doi: 10.1016/j.cell.2010.02.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14:1296–1302. doi: 10.1016/j.cub.2004.06.054. [DOI] [PubMed] [Google Scholar]
  99. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–1101. doi: 10.1126/science.1106148. [DOI] [PubMed] [Google Scholar]
  100. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006;22:159–168. doi: 10.1016/j.molcel.2006.03.029. [DOI] [PubMed] [Google Scholar]
  101. Schalm SS, Blenis J. Identification of a conserved motif required for mTOR signaling. Curr Biol. 2002;12:632–639. doi: 10.1016/s0960-9822(02)00762-5. [DOI] [PubMed] [Google Scholar]
  102. Schalm SS, Fingar DC, Sabatini DM, Blenis J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol. 2003;13:797–806. doi: 10.1016/s0960-9822(03)00329-4. [DOI] [PubMed] [Google Scholar]
  103. Schieke SM, Phillips D, McCoy JP, Jr, Aponte AM, Shen RF, Balaban RS, Finkel T. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem. 2006;281:27643–27652. doi: 10.1074/jbc.M603536200. [DOI] [PubMed] [Google Scholar]
  104. Sekulic A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 2000;60:3504–3513. [PubMed] [Google Scholar]
  105. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009;326:140–144. doi: 10.1126/science.1177221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell. 2010;40:310–322. doi: 10.1016/j.molcel.2010.09.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Shah OJ, Hunter T. Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis. Mol Cell Biol. 2006;26:6425–6434. doi: 10.1128/MCB.01254-05. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6:91–99. doi: 10.1016/j.ccr.2004.06.007. [DOI] [PubMed] [Google Scholar]
  109. Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell. 2006;11:583–589. doi: 10.1016/j.devcel.2006.08.013. [DOI] [PubMed] [Google Scholar]
  110. Smith EM, Finn SG, Tee AR, Browne GJ, Proud GG. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J Biol Chem. 2005;280:18717–18727. doi: 10.1074/jbc.M414499200. [DOI] [PubMed] [Google Scholar]
  111. Sun Y, Fang Y, Yoon MS, Zhang C, Roccio M, Zwartkruis FJ, Armstrong M, Brown HA, Chen J. Phospholipase D1 is an effector of Rheb in the mTOR pathway. Proc Natl Acad Sci USA. 2008;105:8286–8291. doi: 10.1073/pnas.0712268105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Tang H, Hornstein E, Stolovich M, Levy G, Livingstone M, Templeton D, Avruch J, Meyuhas O. Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by rapamycin, and is independent of S6K1 and rpS6 phosphorylation. Mol Cell Biol. 2001;21:8671–8683. doi: 10.1128/MCB.21.24.8671-8683.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc NatlAcad Sci USA. 2002;99:13571–13576. doi: 10.1073/pnas.202476899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol. 2003;13:1259–1268. doi: 10.1016/s0960-9822(03)00506-2. [DOI] [PubMed] [Google Scholar]
  115. Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jeno P, Arrieumerlou C, Hall MN. PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS ONE. 2007;2:e1217. doi: 10.1371/journal.pone.0001217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009;284:8023–8032. doi: 10.1074/jbc.M900301200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Tzatsos A. Raptor binds the SAIN (Shc and IRS-1 NPXY binding) domain of insulin receptor substrate-1 (IRS-1) and regulates the phosphorylation of IRS-1 at Ser-636/639 by mTOR. J Biol Chem. 2009;284:22525–22534. doi: 10.1074/jbc.M109.027748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  118. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature. 2004;431:200–205. doi: 10.1038/nature02866. [DOI] [PubMed] [Google Scholar]
  119. Veenstra-VanderWeele J, Blakely RD. Networking in autism: Leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology. 2012;37:196–212. doi: 10.1038/npp.2011.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Vega-Rubin-de-Celis S, Abdallah Z, Kinch L, Grishin NV, Brugarolas J, Zhang X. Structural analysis and functional implications of the negative mTORC1 regulator REDD 1. Biochemistry. 2010;49:2491–2501. doi: 10.1021/bi902135e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975;28:721–726. doi: 10.7164/antibiotics.28.721. [DOI] [PubMed] [Google Scholar]
  122. Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 2001;20:4370–4379. doi: 10.1093/emboj/20.16.4370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Wang L, Harris TE, Lawrence JC., Jr Regulation of proline-rich Akt substrate of 40kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J Biol Chem. 2008;283:15619–15627. doi: 10.1074/jbc.M800723200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ, Kim DH. PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem. 2007;282:25604–25612. doi: 10.1074/jbc.M704343200. [DOI] [PubMed] [Google Scholar]
  125. Yamada O, Ozaki K, Nakatake M, Kakiuchi Y, Akiyama M, Mitsuishi T, Kawauchi K, Matsuoka R. Akt and PKC are involved not only in upregulation of telomerase activity but also in cell differentiation-related function via mTORC2 in leukemia cells. Histochem Cell Biol. 2010;134:555–563. doi: 10.1007/s00418-010-0764-0. [DOI] [PubMed] [Google Scholar]
  126. Yamnik RL, Holz MK. mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor alpha serine 167 phosphorylation. FEBS Lett. 2010;584:124–128. doi: 10.1016/j.febslet.2009.11.041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem. 2009;284:6361–6369. doi: 10.1074/jbc.M807532200. [DOI] [PubMed] [Google Scholar]
  128. Ye L, Varamini B, Lamming DW, Sabatini DM, Baur JA. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Front Genet. 2012;3:177. doi: 10.3389/fgene.2012.00177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. Yellen P, Saqcena M, Salloum D, Feng J, Preda A, Xu L, Rodrik-Outmezguine V, Foster DA. High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex 1 and suppressing phosphorylation of 4E-BP1. Cell Cycle. 2011;10:3948–3956. doi: 10.4161/cc.10.22.18124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  130. Yip CK, Murata K, Walz T, Sabatini DM, Kang SA. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell. 2010;38:768–774. doi: 10.1016/j.molcel.2010.05.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  131. Yu Y, Yoon SO, Poulogiannis G, Yang Q, Ma XM, Villen J, Kubica N, Hoffman GR, Cantley LC, Gygi SP, Blenis J. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science. 2011;332:1322–1326. doi: 10.1126/science.1199484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  132. Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, Vazquez F, Carpenter CL, Kwiatkowski DJ. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest. 2003;112:1223–1233. doi: 10.1172/JCI17222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  133. Zhang F, Lazorchak AS, Liu D, Chen F, Su B. Inhibition of the mTORC2 and chaperone pathways to treat leukemia. Blood. 2012;119:6080–6088. doi: 10.1182/blood-2011-12-399519. [DOI] [PubMed] [Google Scholar]
  134. Zhou J, Blundell J, Ogawa S, Kwon CH, Zhang W, Sinton C, Powell CM, Parada LF. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci. 2009;29:1773–1783. doi: 10.1523/JNEUROSCI.5685-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  135. Zid BM, Rogers AN, Katewa SD, Vargas MA, Kolipinski MC, Lu TA, Benzer S, Kapahi P. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell. 2009;139:149–160. doi: 10.1016/j.cell.2009.07.034. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES