Snapshot: Mtorc1 Signaling at the Lysosomal Surface Liron Bar-Peled and David M

eebr7 02©02Esve n. DOI http://dx.doi.org/10.1016/j.cell.2012.11.038 Cell 151 , December 7, 2012©2012 Elsevier Inc. 1390 SnapShot: mTORC1 Signaling at the Lysosomal Surface Liron Bar-Peled and David M. Sabatini Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

Nutrient signaling Wnt Growth Leu signaling factor signaling TNF signaling Amino Gln Wnt Tyrosine acids Frizzled IGF kinase TNFD receptor TNF receptor DNA Energy levels O levels SLC1A5 SLC7A5 2 damage ATP/AMP PIP2 Pten Amino acid mTORC1 Dsh1 IRS1 transporter Gln (inactive) GRB2 SOS PI3K PIP3 Gln Redd1 p53 LKB1 GEF GSK3 activity Leu GTP Ras NF1 PDK1 GAP Sestrin Movement to the activity RagAGTP lysosomal surface Movement AMPK Raf GDP away from Rapamycin RagA the lysosomal surface FKBP12 Mek

Erk1/2 Rsk1 Akt1 IKK` v-ATPase GEF activity CYTOPLASM

RagAGTP mTORC1 Ragulator GTP GAP activity GDP TSC complex RagC (active) Rheb

Tumor suppressor Oncogene mTORC1 substrate ? Growth DOWNSTREAM CELLULAR PROGRAMS REGULATED BY mTORC1 ACTIVITY

See online version for legend and references. and legend for version online See S6K1 Amino acids LYSOSOME Protein synthesis 4EBP1 COMPLEXES AT THE LYSOSOMAL SURFACE HIF1_ Energy metabolism A B A E E G G

pras40 deptor Lysosome biogenesis A BB MP1 HBXIP TSC1 TBC1D7 TFEB p14 C7orf59 raptor mLST8 H C Lipin-1 Lipid D p18 biosynthesis a d F mTOR TSC2 SREBP1/2 c cc ATG13 FIP200 Autophagy Lysosomal v-ATPase Ragulator complex mTORC1 TSC complex ULK1 SnapShot: mTORC1 Signaling at the Lysosomal Surface Liron Bar-Peled and David M. Sabatini Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

In mammals, the mTOR complex 1 (mTORC1) ser/thr kinase regulates cellular and organismal growth in response to a variety of environmental and intracellular stimuli. Amino acid levels mediate the first step in the bipartite activation of mTORC1 by promoting its translocation from a cytosolic compartment to the lysosomal surface. By a poorly understood mechanism, amino acid sensing initiates from within the lysomal lumen and, in a process requiring the v-ATPase, activates the GEF activity of the Ragulator complex toward RagA within the heterodimeric Rag GTPases. Upon GTP binding, RagA recruits mTORC1 to the lysosomal surface, allowing it to interact with the small GTPase Rheb, a potent stimulator of mTORC1 kinase activity. Regulation of nucleotide binding state of Rheb by the tumor suppressor TSC, which is found at the lysosomal surface, is the second step in the activation of mTORC1. Many of the environmental and intracellular cues that impinge on mTORC1 funnel through TSC and regulate its GAP activity toward Rheb. Among them, growth factor signaling through the PI3K or Ras pathways leads to the activation of the protein kinases Akt and Rsk1, respectively, which phosphorylate and inhibit TSC function. The AMPK pathway becomes activated upon low energy levels and in a p53-dependent manner by DNA damage, leading to phosphorylation and activation of TSC and phosphorylation and inactivation of mTORC1. Reduction in oxygen levels induces Redd1 expression, which by an ill-defined process maintains TSC function. Once activated, mTORC1 enables growth by promoting anabolic programs while repressing catabolic processes. mTORC1 phosphorylates key effectors such as z1 and 4EBP1 to activate translation and inhibits autophagy by phosphorylating and inactivating ATG13 and ULK1. As a master regulator of cell metabolism, deregulation of the mTORC1 pathway is common in many human diseases. Cancers with aberrant mTORC1 activity, such as tuberous sclerosis and advanced renal cell carcinoma, are increasingly treated with analogs of the mTORC1 inhibitor Rapamycin. Furthermore, overactivation of this pathway leads to the downregulation of IRS1 and progression of type 2 diabetes. Although the mTORC1 pathway is absolutely required for mammalian development, reduction of mTORC1 activity in mice models through pharmacological inhibition not only enhances adult stem cell numbers, function, or both, but also extends murine life span.

Abbreviations mTOR, mechanistic target of rapamycin; raptor, regulatory associated protein of mTOR; mLST8, mammalian lethal with SEC13 protein 8; pras40, proline-rich Akt substrate 40 kDa; Rheb, ras homolog enriched in brain; TSC, tuberous sclerosis complex; Rag, ras-related GTP binding; MP1, MAPK scaffold protein 1; HBXIP, hepatitis B virus X-interacting protein; v-ATPase, vacuolar H+-adenosine triphosphatase ATPase; GEF, guanine nucleotide exchange factor; GAP, GTPase-activating protein; ULK1, unc-51-like kinase 1; ATG13, autophagy-related protein 13; FIP200, FAK family kinase-interacting protein of 200 kDA; S6K1, p70 ribosomal S6 kinase 1; 4EBP1, 4E-binding protein 1; Redd, protein regulated in development and DNA damage response 1; TFEB, transcription factor EB; HIF1a, hypoxia-inducible factor 1a; LKB1, serine/threonine-protein kinase STK11; SREBP1, sterol regulatory element binding protein-1; AMPK, 5´-AMP-activated protein kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; PI3K, phosphatidylinositol 3-kinase; GRB2, growth factor receptor-bound protein 2; SOS, son-of-sevenless; NF1, neurofibromin 1; PDK1, phosphoinositide dependent kinase 1; IRS1, insulin receptor substrate 1; IGF, insulin-like growth factor; TNFa, tumor necrosis factor a; IKKB, inhibitor of nuclear factor k-B kinase subunit b; WNT, wingless; Dsh1, dishevelled 1; GSK3, glycogen synthase kinase 3; TK, tyrosine kinase; SLC1A5, solute carrier family 1 member 5; SLC7A5, solute carrier family 7 member 5; FKBP12, FK506-binding protein 12 KDa.

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