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The Evolution of the TOR Pathway and Its Role in Cancer

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The Evolution of the TOR Pathway and Its Role in Cancer Oncogene (2013) 32, 3923–3932 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW The evolution of the TOR pathway and its role in cancer EM Beauchamp1 and LC Platanias1,2 The target of rapamycin (TOR) pathway is highly conserved among eukaryotes and has evolved to couple nutrient sensing to cellular growth. TOR is found in two distinct signaling complexes in cells, TOR complex 1 (TORC1) and TOR complex 2 (TORC2). These complexes are differentially regulated and act as effectors for the generation of signals that drive diverse cellular processes such as growth, proliferation, protein synthesis, rearrangement of the cytoskeleton, autophagy, metabolism and survival. Mammalian TOR (mTOR) is very important for development in embryos, while in adult organisms it is linked to aging and lifespan effects. In humans, the mTOR pathway is implicated in the tumorigenesis of multiple cancer types and its deregulation is associated with familial cancer syndromes. Because of its high biological relevance, different therapeutic strategies have been developed to target this signaling cascade, resulting in the emergence of unique pharmacological inhibitors that are either already approved for use in clinical oncology or currently under preclinical or clinical development. Multimodal treatment strategies that simultaneously target multiple nodes of the pathway and/or negative feedback regulatory loops may ultimately provide the best therapeutic advantage in targeting this pathway for the treatment of malignancies. Oncogene (2013) 32, 3923–3932; doi:10.1038/onc.2012.567; published online 17 December 2012 Keywords: mTOR; cancer; leukemia INTRODUCTION (PRAS40), DEP domain-containing mTOR-interacting protein (DEP- The target of rapamycin (TOR) pathway is only found in TOR), and mammalian lethal with SEC13 protein 8 (mLST8), with eukaryotes and is conserved in multiple species from yeast to RAPTOR and PRAS40 being the unique components, while the rest 15 mammals.1 It was originally discovered by the recognition of are shared with mTORC2. The major substrates for mTORC1 are mutations that conferred resistance to the growth inhibitory the p70 S6 kinase (S6K) and the translational repressor eIF4E- 16–18 effects of rapamycin in the yeast, Saccharomyces cerevisiae.2 The binding protein 1 (4E-BP1). mTORC1 activity is required for mammalian TOR (mTOR) was identified later, when multiple phosphorylation and subsequent activation of S6K, which then groups cloned the mTOR gene in mouse, human and rat.3–7 TOR is phosphorylates or binds proteins such as eukaryotic elongation present in at least two unique complexes with other proteins, TOR factor 2 kinase (eEF2K), S6K Aly/REF-like target (SKAR), ribosomal complex 1 (TORC1) and TOR complex 2 (TORC2).8,9 These protein S6 (rpS6) and eukaryotic initiation factor 4B (eIF4B), 19–21 complexes are differentially regulated by distinct upstream ultimately promoting translation initiation and elongation. signals, and their activation and functional engagement results Recently, a new substrate for S6K has been discovered, glioma- in control of distinct downstream effector pathways. Nutrients, associated oncogene homolog 1 (GLI1), which links mTORC1 to 22 growth factors, cellular energy and stress pathways regulate Hedgehog signaling. Thus, several distinct substrates are TORC1, while TORC2 appears to be primarily regulated by growth phosphorylated by S6K, resulting in activation of diverse factors.8,10,11 Recently, it was also shown that interferons (IFNs), downstream signals, reflecting a multifaceted role for S6K as a which are cytokines with growth inhibitory activities, could also major branch of the mTOR pathway. mTORC1 also phosphorylates activate mTORC112 and mTORC2.13 Other work has demonstrated and deactivates 4E-BP1, which in its unphosphorylated form that mTORC2 is inhibited by ER stress through phosphorylation of inhibits mRNA translation initiation by binding to the eukaryotic 23–25 rapamycin-insensitive companion of mTOR (RICTOR) by glycogen initiation factor 4E (eIF4E). Upon phosphorylation by mTORC1, synthase kinase 3b (GSK-3b).14 These complexes have distinct 4E-BP1 dissociates from eIF4E and allows eIF4E binding to eIF4G, 24–26 functions, with TORC1 primarily acting as regulator of cell growth, so initiation of translation can occur. protein synthesis and autophagy, whereas TORC2 controls cellular mTORC1 activity can be controlled by multiple growth 12,27–31 events important for cytoskeletal rearrangement, cell survival, factor and cytokine pathways. AKT activates mTORC1 via cell-cycle progression and metabolism.15 phosphorylation and inhibition of tuberous sclerosis 1/2 (TSC1/2), which leads to RAS homolog enriched in brain (RHEB) activation.27,30 Extracellular signal-related kinase (ERK) and 90 kDa ribosomal protein S6 kinase 1 (RSK1), have been also REGULATION AND FUNCTION OF mTORC1 AND mTORC2 shown to phosphorylate/inactivate the TSC1/2 complex, mTORC1 suggesting that they may also regulate mTORC1.29,31 The WNT mTORC1 in mammals is composed of regulatory-associated pathway can also control mTORC1 activity by inhibition of GSK-3b, 32 protein of mTOR (RAPTOR), 40 kDa proline-rich AKT substrate which inhibits mTORC1 via phosphorylation/activation of TSC2. 1Robert H Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA and 2Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA. Correspondence: Dr LC Platanias, Robert H Lurie Comprehensive Cancer Center, 303 East Superior Street, Lurie 3-107, Chicago, IL 60611, USA. E-mail: [email protected] Received 7 September 2012; revised 8 October 2012; accepted 8 October 2012; published online 17 December 2012 Evolution of TOR pathway and its role in cancer EM Beauchamp and LC Platanias 3924 Also, mTORC1 can be regulated by cellular energy through AMP- S6K.51,54 Whether VPS34 directly activates S6K or mTORC1 is not activated protein kinase (AMPK).33,34 AMPK can inhibit mTORC1 by known, but mTORC1 has been co-immunoprecipitated with phosphorylating and activating TSC2.32,35 AMPK has been also VPS34,48 suggesting a regulatory effect at the mTORC1 level. shown to directly phosphorylate RAPTOR, and affect mTORC1 Under energy stress, AMPK is also able to inhibit VPS34, which complex formation.36 The AMPK phosphorylation sites in RAPTOR indicates that both amino acids and energy levels can regulate are highly conserved in all eukaryotes, even in those lacking the mTORC1 through VPS34.54 The role of VPS34 in autophagy and TSC complex, indicating it was probably the first mechanism to mTORC1 signaling seems counterintuitive as mTORC1 is link AMPK to TOR.36 It should be noted that a direct interaction established as a key negative regulator of autophagy48 between RAPTOR and AMPK, however, has only been shown in (Figure 1). Thus, the precise regulation and engagement of mammals.36 mTORC1 can be inhibited by DNA damage or other VPS34 in both processes remains to be investigated. It should be cellular stress signals through the p53 response by upregulating noted, that both mTORC1 and mTORC2 can regulate autophagy, the expression of negative regulators of PI3K/mTOR.37 Also p53 but only mTORC1 does so directly (Figure 1). Whereas AMPK can has been shown to upregulate the genes for Sestrin1 and Sestrin2, phosphorylate ULK1 to activate autophagy, mTORC1 can directly which activate AMPK, thus inhibiting mTORC1.38 Another potential phosphorylate ULK1 to inhibit autophagy.55,56 On the other hand, regulator of mTORC1 is PRAS40. This protein was originally mTORC2 has been reported to inhibit autophagy indirectly, via discovered as a substrate for AKT,39,40 and then subsequently repression by the AKT/forkhead box protein O (FOXO) axis of shown to be a component and substrate of mTORC1.41–44 There certain genes encoding for elements of the autophagic have been studies to show that it can act as either a negative or machinery.57 positive regulator of mTOR signaling, likely depending on the context of engagement and the activation or interference of other signaling elements.41,42,44–47 Therefore, its specific role in mTOR mTORC2 signaling remains to be clarified and precisely defined. The mTORC2 complex is composed of mammalian stress-activated The precise mechanism of mTORC1 regulation by amino acids is map kinase-interacting protein 1 (mSIN1), protein observed with not known. However, it has been established that the amino acid RICTOR (PROTOR), RICTOR, DEPTOR and mLST8, where the unique levels can affect mTORC1 activity through VPS34 and RAG complex components are mSIN1, PROTOR and RICTOR.15 mTORC2 GTPases.15,48 Amino acids cause a switch of RAGs to their active phosphorylates AGC kinases, such as AKT, serum and conformation by promoting their conversion to their proper glucocorticoid-regulated kinase (SGK) and protein kinase GTP/GDP-bound state.49,50 The active RAGs then bind to RAPTOR C-a (PKCa).58–61 A defining function of the mTORC2 complex is and target mTORC1 to the endosome and lysosome where it can its ability to phosphorylate AKT on the Ser473 (Ser505 in flies) be activated by RHEB in response to amino acids.50 RHEB is residue, priming AKT for further phosphorylation by required for activation of mTORC1 by amino acids independent of 3-phosphoinositide-dependent protein kinase 1 (PDK1) at the the TSC complex, unlike insulin, which requires both RHEB and Thr308 residue.58,60,61 The integrity of RICTOR is essential for such TSC1/2.27,51
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