Energy-Sensing Pathways in Ischemia: The Counterbalance Between AMPK and mTORC

Author(s): Angel Cespedes, Mario Villa, Irene Benito-Cuesta*, Maria J. Perez-Alvarez, Lara Ordoñez, Francisco Wandosell*.

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 45 , 2019


Abstract:

Stroke is an important cause of death and disability, and it is the second leading cause of death worldwide. In humans, middle cerebral artery occlusion (MCAO) is the most common cause of ischemic stroke. The damage occurs due to the lack of nutrients and oxygen contributed by the blood flow.

The present review aims to analyze to what extent the lack of each of the elements of the system leads to damage and which mechanisms are unaffected by this deficiency. We believe that the specific analysis of the effect of lack of each component could lead to the emergence of new therapeutic targets for this important brain pathology.

Keywords: Stroke, Middle Cerebral Artery Occlusion (MCAO), nutrients deprivation, Oxygen-glucose Deprivation (OGD), signaling, mTORC1, AMPK.

[1]
Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989; 20(1): 84-91.
[http://dx.doi.org/10.1161/01.STR.20.1.84] [PMID: 2643202]
[2]
Mhairi MI. New models of focal cerebral ischaemia. Br J Clin Pharmacol 1992; 34(4): 302-8.
[http://dx.doi.org/10.1111/j.1365-2125.1992.tb05634.x] [PMID: 1457262]
[3]
Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet 2008; 371(9624): 1612-23.
[http://dx.doi.org/10.1016/S0140-6736(08)60694-7] [PMID: 18468545]
[4]
Zheng Y, Hou J, Liu J, et al. Inhibition of autophagy contributes to melatonin-mediated neuroprotection against transient focal cerebral ischemia in rats. J Pharmacol Sci 2014; 124(3): 354-64.
[http://dx.doi.org/10.1254/jphs.13220FP] [PMID: 24646622]
[5]
Chen L, Zhang Y, Li D, et al. Everolimus (RAD001) ameliorates vascular cognitive impairment by regulating microglial function via the mTORC1 signaling pathway. J Neuroimmunol 2016; 299: 164-71.
[http://dx.doi.org/10.1016/j.jneuroim.2016.09.008] [PMID: 27725116]
[6]
Lisi L, Aceto P, Navarra P, Dello Russo C. mTOR kinase: a possible pharmacological target in the management of chronic pain. BioMed Res Int 2015; 2015: 394257.
[http://dx.doi.org/10.1155/2015/394257] [PMID: 25685786]
[7]
Guo Z, Cao G, Yang H, et al. A combination of four active compounds alleviates cerebral ischemia-reperfusion injury in correlation with inhibition of autophagy and modulation of AMPK/mTOR and JNK pathways. J Neurosci Res 2014; 92(10): 1295-306.
[http://dx.doi.org/10.1002/jnr.23400] [PMID: 24801159]
[8]
Chen S-D, Wu C-L, Hwang W-C, Yang D-I. More insight into bdnf against neurodegeneration: anti-apoptosis, anti-oxidation, and suppression of autophagy. Int J Mol Sci 2017; 18(3): 545.
[http://dx.doi.org/10.3390/ijms18030545] [PMID: 28273832]
[9]
Pérez-Álvarez MJ, Maza Mdel C, Anton M, Ordoñez L, Wandosell F. Post-ischemic estradiol treatment reduced glial response and triggers distinct cortical and hippocampal signaling in a rat model of cerebral ischemia. J Neuroinflammation 2012; 9: 157.
[http://dx.doi.org/10.1186/1742-2094-9-157] [PMID: 22747981]
[10]
Mateos L, Perez-Alvarez MJ, Wandosell F. Angiotensin II type-2 receptor stimulation induces neuronal VEGF synthesis after cerebral ischemia. Biochim Biophys Acta 2016; 1862(7): 1297-308.
[http://dx.doi.org/10.1016/j.bbadis.2016.03.013] [PMID: 27045356]
[11]
Yecies JL, Manning BD. mTOR links oncogenic signaling to tumor cell metabolism. J Mol Med (Berl) 2011; 89(3): 221-8.
[http://dx.doi.org/10.1007/s00109-011-0726-6] [PMID: 21301797]
[12]
Crowder RJ, Freeman RS. Glycogen synthase kinase-3 beta activity is critical for neuronal death caused by inhibiting phosphatidylinositol 3-kinase or Akt but not for death caused by nerve growth factor withdrawal. J Biol Chem 2000; 275(44): 34266-71.
[http://dx.doi.org/10.1074/jbc.M006160200] [PMID: 10954722]
[13]
Dudek H, Datta SR, Franke TF, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997; 275(5300): 661-5.
[http://dx.doi.org/10.1126/science.275.5300.661] [PMID: 9005851]
[14]
Ohba N, Kiryu-Seo S, Maeda M, Muraoka M, Ishii M, Kiyama H. Transgenic mouse overexpressing the Akt reduced the volume of infarct area after middle cerebral artery occlusion. Neurosci Lett 2004; 359(3): 159-62.
[http://dx.doi.org/10.1016/j.neulet.2004.02.029] [PMID: 15050688]
[15]
Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378(6559): 785-9.
[http://dx.doi.org/10.1038/378785a0] [PMID: 8524413]
[16]
Fishwick KJ, Li RA, Halley P, Deng P, Storey KG. Initiation of neuronal differentiation requires PI3-kinase/TOR signalling in the vertebrate neural tube. Dev Biol 2010; 338(2): 215-25.
[http://dx.doi.org/10.1016/j.ydbio.2009.12.001] [PMID: 20004186]
[17]
Guo W, Jiang H, Gray V, Dedhar S, Rao Y. Role of the integrin-linked kinase (ILK) in determining neuronal polarity. Dev Biol 2007; 306(2): 457-68.
[http://dx.doi.org/10.1016/j.ydbio.2007.03.019] [PMID: 17490631]
[18]
Ménager C, Arimura N, Fukata Y, Kaibuchi K. PIP3 is involved in neuronal polarization and axon formation. J Neurochem 2004; 89(1): 109-18.
[http://dx.doi.org/10.1046/j.1471-4159.2004.02302.x] [PMID: 15030394]
[19]
Yan D, Guo L, Wang Y. Requirement of dendritic Akt degradation by the ubiquitin-proteasome system for neuronal polarity. J Cell Biol 2006; 174(3): 415-24.
[http://dx.doi.org/10.1083/jcb.200511028] [PMID: 16864652]
[20]
Yoshimura T, Arimura N, Kawano Y, Kawabata S, Wang S, Kaibuchi K. Ras regulates neuronal polarity via the PI3-kinase/Akt/GSK-3beta/CRMP-2 pathway. Biochem Biophys Res Commun 2006; 340(1): 62-8.
[http://dx.doi.org/10.1016/j.bbrc.2005.11.147] [PMID: 16343426]
[21]
Lovejoy CA, Cortez D. Common mechanisms of PIKK regulation. DNA Repair (Amst) 2009; 8(9): 1004-8.
[http://dx.doi.org/10.1016/j.dnarep.2009.04.006] [PMID: 19464237]
[22]
Kok K, Geering B, Vanhaesebroeck B. Regulation of phosphoinositide 3-kinase expression in health and disease. Trends Biochem Sci 2009; 34(3): 115-27.
[http://dx.doi.org/10.1016/j.tibs.2009.01.003] [PMID: 19299143]
[23]
Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 2010; 11(5): 329-41.
[http://dx.doi.org/10.1038/nrm2882] [PMID: 20379207]
[24]
Vanhaesebroeck B, Stephens L, Hawkins P. PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol 2012; 13(3): 195-203.
[http://dx.doi.org/10.1038/nrm3290] [PMID: 22358332]
[25]
Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007; 129(7): 1261-74.
[http://dx.doi.org/10.1016/j.cell.2007.06.009] [PMID: 17604717]
[26]
Hwang SK, Kim HH. The functions of mTOR in ischemic diseases. BMB Rep 2011; 44(8): 506-11.
[http://dx.doi.org/10.5483/BMBRep.2011.44.8.506] [PMID: 21871173]
[27]
Switon K, Kotulska K, Janusz-Kaminska A, Zmorzynska J, Jaworski J. Molecular neurobiology of mTOR. Neuroscience 2017; 341: 112-53.
[http://dx.doi.org/10.1016/j.neuroscience.2016.11.017] [PMID: 27889578]
[28]
Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature 2013; 497(7448): 217-23.
[http://dx.doi.org/10.1038/nature12122] [PMID: 23636326]
[29]
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(5): 768-74.
[http://dx.doi.org/10.1016/j.molcel.2010.05.017] [PMID: 20542007]
[30]
Aylett CHS, Sauer E, Imseng S, et al. Architecture of human mTOR complex 1. Science 2016; 351(6268): 48-52.
[http://dx.doi.org/10.1126/science.aaa3870] [PMID: 26678875]
[31]
Zhao H, Sapolsky RM, Steinberg GK. Phosphoinositide-3-kinase/akt survival signal pathways are implicated in neuronal survival after stroke. Mol Neurobiol 2006; 34(3): 249-70.
[http://dx.doi.org/10.1385/MN:34:3:249] [PMID: 17308356]
[32]
Dibble CC, Cantley LC. Regulation of mTORC1 by PI3K signaling. Trends Cell Biol 2015; 25(9): 545-55.
[http://dx.doi.org/10.1016/j.tcb.2015.06.002] [PMID: 26159692]
[33]
Dan HC, Ebbs A, Pasparakis M, Van Dyke T, Basseres DS, Baldwin AS. Akt-dependent activation of mTORC1 complex involves phosphorylation of mTOR (mammalian target of rapamycin) by IκB kinase α (IKKα). J Biol Chem 2014; 289(36): 25227-40.
[http://dx.doi.org/10.1074/jbc.M114.554881] [PMID: 24990947]
[34]
Chiang GG, Abraham RT. Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem 2005; 280(27): 25485-90.
[http://dx.doi.org/10.1074/jbc.M501707200] [PMID: 15899889]
[35]
Kovacina KS, Park GY, Bae SS, et al. Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J Biol Chem 2003; 278(12): 10189-94.
[http://dx.doi.org/10.1074/jbc.M210837200] [PMID: 12524439]
[36]
Parmar N, Tamanoi F. Rheb G-Proteins and the Activation of mTORC1. Enzymes 2010; 27: 39-56.
[http://dx.doi.org/10.1016/S1874-6047(10)27003-8] [PMID: 25429186]
[37]
Malik AR, Urbanska M, Macias M, Skalecka A, Jaworski J. Beyond control of protein translation: what we have learned about the non-canonical regulation and function of mammalian target of rapamycin (mTOR). Biochim Biophys Acta 2013; 1834(7): 1434-48.
[http://dx.doi.org/10.1016/j.bbapap.2012.12.010] [PMID: 23277194]
[38]
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149(2): 274-93.
[http://dx.doi.org/10.1016/j.cell.2012.03.017] [PMID: 22500797]
[39]
Li YH, Werner H, Püschel AW. Rheb and mTOR regulate neuronal polarity through Rap1B. J Biol Chem 2008; 283(48): 33784-92.
[http://dx.doi.org/10.1074/jbc.M802431200] [PMID: 18842593]
[40]
Morita T, Sobue K. Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway. J Biol Chem 2009; 284(40): 27734-45.
[http://dx.doi.org/10.1074/jbc.M109.008177] [PMID: 19648118]
[41]
Ruvinsky I, Meyuhas O. Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci 2006; 31(6): 342-8.
[http://dx.doi.org/10.1016/j.tibs.2006.04.003] [PMID: 16679021]
[42]
Gingras AC, Raught B, Gygi SP, et al. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 2001; 15(21): 2852-64.
[PMID: 11691836]
[43]
Carroll M, Borden KL. The oncogene eIF4E: using biochemical insights to target cancer. J Interferon Cytokine Res 2013; 33(5): 227-38.
[http://dx.doi.org/10.1089/jir.2012.0142] [PMID: 23472659]
[44]
Tsukiyama-Kohara K, Poulin F, Kohara M, et al. Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1. Nat Med 2001; 7(10): 1128-32.
[http://dx.doi.org/10.1038/nm1001-1128] [PMID: 11590436]
[45]
Gkogkas CG, Khoutorsky A, Ran I, et al. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 2013; 493(7432): 371-7.
[http://dx.doi.org/10.1038/nature11628] [PMID: 23172145]
[46]
Park Y, Reyna-Neyra A, Philippe L, Thoreen CC. mTORC1 Balances cellular amino acid supply with demand for protein synthesis through post-transcriptional control of ATF4. Cell Rep 2017; 19(6): 1083-90.
[http://dx.doi.org/10.1016/j.celrep.2017.04.042] [PMID: 28494858]
[47]
Lim KH, Counter CM. Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer Cell 2005; 8(5): 381-92.
[http://dx.doi.org/10.1016/j.ccr.2005.10.014] [PMID: 16286246]
[48]
Ma L, Teruya-Feldstein J, Bonner P, et al. Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase mediated mTOR activation in tuberous sclerosis and human cancer. Cancer Res 2007; 67(15): 7106-12.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4798] [PMID: 17671177]
[49]
Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 2014; 15(3): 155-62.
[http://dx.doi.org/10.1038/nrm3757] [PMID: 24556838]
[50]
Poels J, Spasić MR, Callaerts P, Norga KK. Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy. BioEssays 2009; 31(9): 944-52.
[http://dx.doi.org/10.1002/bies.200900003] [PMID: 19644919]
[51]
Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17(6): 596-603.
[http://dx.doi.org/10.1016/j.ceb.2005.09.009] [PMID: 16226444]
[52]
Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 2005; 1(1): 15-25.
[http://dx.doi.org/10.1016/j.cmet.2004.12.003] [PMID: 16054041]
[53]
Agarwal S, Tiwari SK, Seth B, et al. Activation of autophagic flux against xenoestrogen bisphenol-a-induced hippocampal neurodegeneration via AMP kinase (AMPK)/Mammalian target of rapamycin (mTOR) pathways. J Biol Chem 2015; 290(34): 21163-84.
[http://dx.doi.org/10.1074/jbc.M115.648998] [PMID: 26139607]
[54]
Inoki K, Ouyang H, Zhu T, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006; 126(5): 955-68.
[http://dx.doi.org/10.1016/j.cell.2006.06.055] [PMID: 16959574]
[55]
Takei N, Nawa H. mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci 2014; 7: 28.
[http://dx.doi.org/10.3389/fnmol.2014.00028] [PMID: 24795562]
[56]
Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115(5): 577-90.
[http://dx.doi.org/10.1016/S0092-8674(03)00929-2] [PMID: 14651849]
[57]
Kimura N, Tokunaga C, Dalal S, et al. A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 2003; 8(1): 65-79.
[http://dx.doi.org/10.1046/j.1365-2443.2003.00615.x] [PMID: 12558800]
[58]
Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 2007; 403(1): 139-48.
[http://dx.doi.org/10.1042/BJ20061520] [PMID: 17147517]
[59]
Kuwako KI, Okano H. Versatile roles of lkb1 kinase signaling in neural development and homeostasis. Front Mol Neurosci 2018; 11: 354.
[http://dx.doi.org/10.3389/fnmol.2018.00354] [PMID: 30333724]
[60]
Green MF, Scott JW, Steel R, Oakhill JS, Kemp BE, Means AR. Ca2+/Calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation. J Biol Chem 2011; 286(32): 28066-79.
[http://dx.doi.org/10.1074/jbc.M111.251504] [PMID: 21669867]
[61]
Burkewitz K, Zhang Y, Mair WB. AMPK at the nexus of energetics and aging. Cell Metab 2014; 20(1): 10-25.
[http://dx.doi.org/10.1016/j.cmet.2014.03.002] [PMID: 24726383]
[62]
Hardie DG, Schaffer BE, Brunet A. AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol 2016; 26(3): 190-201.
[http://dx.doi.org/10.1016/j.tcb.2015.10.013] [PMID: 26616193]
[63]
Shaw RJ, Bardeesy N, Manning BD, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004; 6(1): 91-9.
[http://dx.doi.org/10.1016/j.ccr.2004.06.007] [PMID: 15261145]
[64]
Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 2004; 18(13): 1533-8.
[http://dx.doi.org/10.1101/gad.1199104] [PMID: 15231735]
[65]
Habegger KM, Hoffman NJ, Ridenour CM, Brozinick JT, Elmendorf JS. AMPK enhances insulin-stimulated GLUT4 regulation via lowering membrane cholesterol. Endocrinology 2012; 153(5): 2130-41.
[http://dx.doi.org/10.1210/en.2011-2099] [PMID: 22434076]
[66]
Tang BL. Sirt1 and the mitochondria. Mol Cells 2016; 39(2): 87-95.
[http://dx.doi.org/10.14348/molcells.2016.2318] [PMID: 26831453]
[67]
Schieke SM, Phillips D, McCoy JP Jr, et al. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 2006; 281(37): 27643-52.
[http://dx.doi.org/10.1074/jbc.M603536200] [PMID: 16847060]
[68]
Brugarolas J, Lei K, Hurley RL, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18(23): 2893-904.
[http://dx.doi.org/10.1101/gad.1256804] [PMID: 15545625]
[69]
Reiling JH, Hafen E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 2004; 18(23): 2879-92.
[http://dx.doi.org/10.1101/gad.322704] [PMID: 15545626]
[70]
Sofer A, Lei K, Johannessen CM, Ellisen LW. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol 2005; 25(14): 5834-45.
[http://dx.doi.org/10.1128/MCB.25.14.5834-5845.2005] [PMID: 15988001]
[71]
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(2): 239-51.
[http://dx.doi.org/10.1101/gad.1617608] [PMID: 18198340]
[72]
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 REDD1. Biochemistry 2010; 49(11): 2491-501.
[http://dx.doi.org/10.1021/bi902135e] [PMID: 20166753]
[73]
Bernardi R, Guernah I, Jin D, et al. PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 2006; 442(7104): 779-85.
[http://dx.doi.org/10.1038/nature05029] [PMID: 16915281]
[74]
Bernardi R, Papa A, Egia A, et al. Pml represses tumour progression through inhibition of mTOR. EMBO Mol Med 2011; 3(5): 249-57.
[http://dx.doi.org/10.1002/emmm.201100130] [PMID: 21387562]
[75]
Li Y, Wang Y, Kim E, et al. Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb. J Biol Chem 2007; 282(49): 35803-13.
[http://dx.doi.org/10.1074/jbc.M705231200] [PMID: 17928295]
[76]
Chen S, Sang N. Hypoxia-Inducible Factor-1: a critical player in the survival strategy of stressed cells. J Cell Biochem 2016; 117(2): 267-78.
[http://dx.doi.org/10.1002/jcb.25283] [PMID: 26206147]
[77]
Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002; 22(20): 7004-14.
[http://dx.doi.org/10.1128/MCB.22.20.7004-7014.2002] [PMID: 12242281]
[78]
Flügel D, Görlach A, Michiels C, Kietzmann T. Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilization in a VHL-independent manner. Mol Cell Biol 2007; 27(9): 3253-65.
[http://dx.doi.org/10.1128/MCB.00015-07] [PMID: 17325032]
[79]
Flügel D, Görlach A, Kietzmann T. GSK-3β regulates cell growth, migration, and angiogenesis via Fbw7 and USP28-dependent degradation of HIF-1α. Blood 2012; 119(5): 1292-301.
[http://dx.doi.org/10.1182/blood-2011-08-375014] [PMID: 22144179]
[80]
Cassavaugh JM, Hale SA, Wellman TL, Howe AK, Wong C, Lounsbury KM. Negative regulation of HIF-1α by an FBW7-mediated degradation pathway during hypoxia. J Cell Biochem 2011; 112(12): 3882-90.
[http://dx.doi.org/10.1002/jcb.23321] [PMID: 21964756]
[81]
Tymianski M. Emerging mechanisms of disrupted cellular signaling in brain ischemia. Nat Neurosci 2011; 14(11): 1369-73.
[http://dx.doi.org/10.1038/nn.2951] [PMID: 22030547]
[82]
Soria FN, Pérez-Samartín A, Martin A, et al. Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage. J Clin Invest 2014; 124(8): 3645-55.
[http://dx.doi.org/10.1172/JCI71886] [PMID: 25036707]
[83]
Sancak Y, Peterson TR, Shaul YD, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008; 320(5882): 1496-501.
[http://dx.doi.org/10.1126/science.1157535] [PMID: 18497260]
[84]
Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007; 25(6): 903-15.
[http://dx.doi.org/10.1016/j.molcel.2007.03.003] [PMID: 17386266]
[85]
Bar-Peled L, Sabatini DM. Regulation of mTORC1 by amino acids. Trends Cell Biol 2014; 24(7): 400-6.
[http://dx.doi.org/10.1016/j.tcb.2014.03.003] [PMID: 24698685]
[86]
Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 2012; 150(6): 1196-208.
[http://dx.doi.org/10.1016/j.cell.2012.07.032] [PMID: 22980980]
[87]
Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 2011; 334(6056): 678-83.
[http://dx.doi.org/10.1126/science.1207056] [PMID: 22053050]
[88]
Rebsamen M, Pochini L, Stasyk T, et al. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 2015; 519(7544): 477-81.
[http://dx.doi.org/10.1038/nature14107] [PMID: 25561175]
[89]
Chantranupong L, Scaria SM, Saxton RA, et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 2016; 165(1): 153-64.
[http://dx.doi.org/10.1016/j.cell.2016.02.035] [PMID: 26972053]
[90]
Lee JH, Cho US, Karin M. Sestrin regulation of TORC1: Is Sestrin a leucine sensor? Sci Signal 2016; 9(431): re5.
[http://dx.doi.org/10.1126/scisignal.aaf2885] [PMID: 27273098]
[91]
Kimball SR, Gordon BS, Moyer JE, Dennis MD, Jefferson LS. Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation. Cell Signal 2016; 28(8): 896-906.
[http://dx.doi.org/10.1016/j.cellsig.2016.03.008] [PMID: 27010498]
[92]
Wolfson RL, Chantranupong L, Saxton RA, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 2016; 351(6268): 43-8.
[http://dx.doi.org/10.1126/science.aab2674] [PMID: 26449471]


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VOLUME: 25
ISSUE: 45
Year: 2019
Page: [4763 - 4770]
Pages: 8
DOI: 10.2174/1381612825666191210152156
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