A critical kinase cascade in neurological disorders: PI3K, Akt and mTOR

Future Neurology

Volumn 7, Issue 6, 2012, Pages 733-748

  Chong, Zhao Zhong ^a   Shang, Yan Chen ^a   Wang, Shaohui ^a   Maiese, Kenneth ^a,b  

^a New Jersey Health Sciences University   (United States)

^b RUTGERS CANCER INSTITUTE OF NEW JERSEY   (United States)

Author keywords

Akt; Alzheimers disease; apoptosis; autophagy; Huntingtons disease; mammalian target of rapamycin; mTOR; Parkinsons disease; PI3K; stroke; trauma

Indexed keywords

ALPHA SYNUCLEIN; AMYLOID BETA PROTEIN; HEAT SHOCK PROTEIN; HUNTINGTIN; LEVODOPA; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN REDD1; RAPAMYCIN; RETINOBLASTOMA PROTEIN; RETINOBLASTOMA TUMOR SUPPRESSOR INDUCIBLE COILED COIL 1; S6 KINASE; TEMSIROLIMUS; UNCLASSIFIED DRUG;

ACUTE CENTRAL NERVOUS SYSTEM INJURY; ALZHEIMER DISEASE; APOPTOSIS; AUTOPHAGY; CELL FATE; CEREBROVASCULAR ACCIDENT; DISEASE ASSOCIATION; DRUG TARGETING; ENZYME ACTIVATION; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; ENZYME REGULATION; EPILEPSY; HUMAN; HUNTINGTON CHOREA; INTRACELLULAR SIGNALING; NERVOUS SYSTEM INJURY; NEUROLOGIC DISEASE; NEUROPATHOLOGY; NEUROPROTECTION; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW; SPINAL CORD INJURY;

EID: 84868646977     PISSN: 14796708     EISSN: 17486971     Source Type: Journal    
DOI: 10.2217/fnl.12.72     Document Type: Review

References (166)

1. Chong ZZ, Maiese K. The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversifed control of cell growth, infammation, and injury. Histol. Histopathol. 22(11), 1251-1267 (2007). (Pubitemid 47470319)
2. Lopez-Ruiz P, Rodriguez-Ubreva J, Cariaga AE, Cortes MA, Colas B. SHP-1 in cell-cycle regulation. Anticancer Agents Med. Chem. 11(1), 89-98 (2011).
3. Chong ZZ, Li F, Maiese K. Activating Akt and the brain's resources to drive cellular survival and prevent infammatory injury. Histol. Histopathol. 20(1), 299-315 (2005). (Pubitemid 40029007)
4. Cheng Z, White MF. Targeting Forkhead box O1 from the concept to metabolic diseases: lessons from mouse models. Antioxid. Redox Signal 14(4), 649-661 (2011).
5. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 13(22), 2905-2927. (1999).
6. Chong ZZ, Shang YC, Zhang L, Wang S, Maiese K. Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. Oxid. Med. Cell Longev. 3(6), 374-391 (2010).
7. Huang X, Zhang H, Yang J et al. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol. Dis. 40(1), 193-199 (2010).
8. Chong ZZ, Maiese K. Mammalian target of rapamycin signaling in diabetic cardiovascular disease. Cardiovasc. Diabetol. 11(1), 45 (2012).
9. Reynolds THT, Bodine SC, Lawrence JC Jr. Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J. Biol. Chem. 277(20), 17657-17662 (2002). (Pubitemid 34967569)
10. Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC Jr. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc. Natl Acad. Sci. USA 95(13), 7772-7777 (1998). (Pubitemid 28293329)
11. Soliman GA, Acosta-Jaquez HA, Dunlop EA et al. mTOR Ser-2481 autophosphorylation monitors mTORC-specifc catalytic activity and clarifes rapamycin mechanism of action. J. Biol. Chem. 285(11), 7866-7879 (2010).
12. Ekim B, Magnuson B, Acosta-Jaquez HA, Keller JA, Feener EP, Fingar DC. mTOR kinase domain phosphorylation promotes mTORC1 signaling, cell growth, and cell cycle progression. Mol. Cell Biol. 31(14), 2787-2801 (2011).
13. Chong ZZ, Shang YC, Wang S, Maiese K. Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin. Prog. Neurobiol. doi:10.1016/j. pneurobio.2012.08.001 (2012) (Epub ahead of print).
14. Loewith R, Jacinto E, Wullschleger S et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10(3), 457-468 (2002). (Pubitemid 35284167)
15. Chong ZZ, Shang YC, Maiese K. Cardiovascular disease and mTOR signaling. Trends Cardiovasc. Med. 21(5), 151-155 (2011).
16. Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J. Antibiot. (Tokyo) 28(10), 727-732 (1975).
17. 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) 28(10), 721-726 (1975).
18. Sarbassov DD, Ali SM, Sengupta S et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22(2), 159-168 (2006).
19. Takahashi T, Hara K, Inoue H et al. Carboxyl-terminal region conserved among phosphoinositide-kinase-related kinases is indispensable for mTOR function in vivo and in vitro. Genes Cells 5(9), 765-775 (2000).
20. Chen J, Zheng XF, Brown EJ, Schreiber SL. Identifcation of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc. Natl Acad. Sci. USA 92(11), 4947-4951 (1995).
21. Abraham RT. mTOR as a positive regulator of tumor cell responses to hypoxia. Curr. Topic. Microbiol. Immunol. 279, 299-319 (2004).
22. Takahara T, Hara K, Yonezawa K, Sorimachi H, Maeda T. Nutrient-dependent multimerization of the mammalian target of rapamycin through the N-terminal HEAT repeat region. J. Biol. Chem. 281(39), 28605-28614 (2006). (Pubitemid 44507003)
23. Wang H, Zhang Q, Wen Q et al. Proline-rich Akt substrate of 40kDa (PRAS40). a novel downstream target of PI3k/Akt signaling pat hway. Cell Signal. 24(1), 17-24 (2012).
24. Wang L, Harris TE, Roth RA, Lawrence JC Jr. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J. Biol. Chem. 282(27), 20036-20044 (2007). (Pubitemid 47100127)
25. Kim DH, Sarbassov DD, Ali SM et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11(4), 895-904 (2003). (Pubitemid 36566312)
26. Peterson TR, Laplante M, Thoreen CC et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137(5), 873-886 (2009).
27. Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol. Cell Biol. 24(1), 200-216 (2004). (Pubitemid 38010048)
28. Jastrzebski K, Hannan KM, Tchoubrieva EB, Hannan RD, Pearson RB. Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors 25(4), 209-226 (2007).
29. 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. 12(4), 502-513 (1998). (Pubitemid 28101013)
30. Bhandari BK, Feliers D, Duraisamy S et al. Insulin regulation of protein translation repressor 4E-BP1, an eIF4E-binding protein, in renal epithelial cells. Kidney Int. 59(3), 866-875 (2001). (Pubitemid 32206849)
31. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat. Rev. Drug Discov. 10(11), 868-880 (2011).
32. Jacinto E, Loewith R, Schmidt A et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6(11), 1122-1128 (2004). (Pubitemid 39468014)
33. Rosner M, Fuchs C, Siegel N, Valli A, Hengstschlager M. Functional interaction of mammalian target of rapamycin complexes in regulating mammalian cell size and cell cycle. Hum. Mol. Genet. 18(17), 3298-3310 (2009).
34. Dada S, Demartines N, Dormond O. mTORC2 regulates PGE2-mediated endothelial cell survival and migration. Biochem. Biophys. Res. Commun. 372(4), 875-879 (2008).
35. Sarbassov DD, Ali SM, Kim DH et al. Rictor, a novel binding partner of mTOR, defnes a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14(14), 1296-1302 (2004). (Pubitemid 38991819)
36. Pearce LR, Sommer EM, Sakamoto K, Wullschleger S, Alessi DR. Protor-1 is required for effcient mTORC2-mediated activation of SGK1 in the kidney. Biochem. J. 436(1), 169-179 (2011).
37. 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. 416(3), 375-385 (2008).
38. Gulhati P, Bowen KA, Liu J et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 71(9), 3246-3256 (2011).
39. Hernandez-Negrete I, Carretero-Ortega J, Rosenfeldt H et al. P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration. J. Biol. Chem. 282(32), 23708-23715 (2007). (Pubitemid 47311970)
40. Zou ZQ, Zhang LN, Wang F, Bellenger J, Shen YZ, Zhang XH. The novel dual PI3K/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells. Mol. Med. Report 5(2), 503-508 (2012).
41. Lee G, Goretsky T, Managlia E et al. Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis. Gastroenterology 139(3), 869-881, 881.e1-9 (2010).
42. Maiese K, Chong ZZ, Shang YC, Hou J. Novel Avenues of Drug Discovery and Biomarkers for Diabetes Mellitus. J. Clin. Pharmacol. 51(2), 128-152 (2011).
43. Ding Z, Liang J, Li J et al. Physical association of PDK1 with AKT1 is suffcient for pathway activation independent of membrane localization and phosphatidylinositol 3 kinase. PLoS ONE 5(3), e9910 (2010).
44. Glidden EJ, Gray LG, Vemuru S, Li D, Harris TE, Mayo MW. Multiple site acetylation of Rictor stimulates mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of Akt protein. J. Biol. Chem. 287(1), 581-588 (2012).
45. Chen JX, Tuo Q, Liao DF, Zeng H. Inhibition of protein tyrosine phosphatase improves angiogenesis via enhancing Ang-1/Tie-2 signaling in diabetes. Exp. Diabetes Res. 2012, 836759 (2012).
46. Deblon N, Bourgoin L, Veyrat-Durebex C et al. Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats. Br. J. Pharmacol. 165(7), 2325-2340 (2012).
47. Hou J, Chong ZZ, Shang YC, Maiese K. Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead traffcking, bad, and mitochondrial caspase activation. Curr. Neurovasc. Res. 7(2), 95-112 (2010).
48. Maiese K, Chong ZZ, Shang YC. Mechanistic insights into diabetes mellitus and oxidative stress. Curr. Med. Chem. 14(16), 1729-1738 (2007). (Pubitemid 47163410)
49. Saha AK, Xu XJ, Lawson E et al. Downregulation of AMPK accompanies leucine-and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle. Diabetes 59(10), 2426-2434 (2010).
50. Koshimizu T, Kawai M, Kondou H et al. Vinculin functions as regulator of chondrogenesis. J. Biol. Chem. 287(19), 15760-15775 (2012).
51. Lu MJ, Chen YS, Huang HS, Ma MC. Erythropoietin alleviates post-ischemic injury of rat hearts by attenuating nitrosative stress. Life Sci. 90(19-20), 776-784 (2012).
52. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4(9), 648-657 (2002). (Pubitemid 34993700)
53. Sato T, Nakashima A, Guo L, Tamanoi F. Specifc activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J. Biol. Chem. 284(19), 12783-12791 (2009).
54. Cai SL, Tee AR, Short JD et al. Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. J. Cell Biol. 173(2), 279-289 (2006).
55. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91(2), 243-252 (1997). (Pubitemid 27456391)
56. Dan HC, Adli M, Baldwin AS. Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha. Cancer Res. 67(13), 6263-6269 (2007). (Pubitemid 47037508)
57. Lee DF, Kuo HP, Chen CT et al. IKK beta suppression of TSC1 links infammation and tumor angiogenesis via the mTOR pathway. Cell 130(3), 440-455 (2007).
58. Oshiro N, Takahashi R, Yoshino K et al. The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J. Biol. Chem. 282(28), 20329-20339 (2007). (Pubitemid 47100038)
59. Wang L, Harris TE, Lawrence JC Jr. Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J. Biol. Chem. 283(23), 15619-15627 (2008).
60. Sancak Y, Thoreen CC, Peterson TR et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25(6), 903-915 (2007). (Pubitemid 46436534)
61. Kovacina KS, Park GY, Bae SS et al. Identifcation of a proline-rich Akt substrate as a 14-13-3 binding partner. J. Biol. Chem. 278(12), 10189-10194 (2003). (Pubitemid 36800278)
62. Vander Haar E, Lee SI, Bandhakavi S, Griffn TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9(3), 316-323 (2007). (Pubitemid 46344611)
63. Maiese K. The many facets of cell injury: angiogenesis to autophagy. Curr. Neurovasc. Res. 9(2), 1-2 (2012).
64. Maiese K, Chong ZZ, Hou J, Shang YC. Oxidative stress: biomarkers and novel therapeutic pathways. Exp. Gerontol. 45(3), 217-234 (2010).
65. Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat. Neurosci. 13(7), 805-811 (2010).
66. Gumy LF, Tan CL, Fawcett J W. The role of local protein synthesis and degradation in axon regeneration. Exp. Neurol. 223(1), 28-37 (2010).
67. Tatton NA. Increased caspase 3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson's disease. Exp. Neurol. 166(1), 29-43 (2000).
68. Broe M, Shepherd CE, Milward EA, Halliday GM. Relationship between DNA fragmentation, morphological changes and neuronal loss in Alzheimer's disease and dementia with Lewy bodies. Acta Neuropathol. 101(6), 616-624 (2001). (Pubitemid 32684761)
69. Louneva N, Cohen JW, Han LY et al. Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer's disease. Am. J. Pathol. 173(5), 1488-1495 (2008).
70. Qin AP, Liu CF, Qin YY et al. Autophagy was activated in injured astrocytes and mildly decreased cell survival following glucose and oxygen deprivation and focal cerebral ischemia. Autophagy 6(6), 738-753 (2010).
71. Wang JY, Xia Q, Chu KT et al. Severe global cerebral ischemia-induced programmed necrosis of hippocampal CA1 neurons in rat is prevented by 3-methyladenine: a widely used inhibitor of autophagy. J. Neuropathol. Exp. Neurol. 70(4), 314-322 (2011).
72. Baba H, Sakurai M, Abe K, Tominaga R. Autophagy-mediated stress response in motor neuron after transient ischemia in rabbits. J. Vasc. Surg. 50(2), 381-387 (2009).
73. Canu N, Tuf R, Serafno AL, Amadoro G, Ciotti MT, Calissano P. Role of the autophagic-lysosomal system on low potassium-induced apoptosis in cultured cerebellar granule cells. J. Neurochem. 92(5), 1228-1242 (2005). (Pubitemid 40344312)
74. Xue L, Fletcher GC, Tolkovsky AM. Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution. Mol. Cell Neurosci. 14(3), 180-198 (1999). (Pubitemid 29449222)
75. Spencer B, Potkar R, Trejo M et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J. Neurosci. 29(43), 13578-13588 (2009).
76. Spilman P, Podlutskaya N, Hart MJ et al. Inhibition of mTOR by rapamycin abolishes cognitive defcits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS ONE 5(4), e9979 (2010).
77. Nopparat C, Porter JE, Ebadi M, Govitrapong P. The mechanism for the neuroprotective effect of melatonin against methamphetamine-induced autophagy. J. Pineal Res. 49(4), 382-389 (2010).
78. Pattingre S, Tassa A, Qu X et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122(6), 927-939 (2005). (Pubitemid 41345209)
79. Luo S, Rubinsztein DC. Apoptosis blocks Beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL. Cell Death Differ. 17(2), 268-277 (2010).
80. Wang S, Chong ZZ, Shang YC, Maiese K. WISP1 (CCN4) autoregulates its expression and nuclear traffcking of beta-catenin during oxidant stress with limited effects upon neuronal autophagy. Curr. Neurovasc. Res. 9(2), 89-99 (2012).
81. Maiese K, Chong ZZ, Hou J, Shang YC. The vitamin nicotinamide: translating nutrition into clinical care. Molecules 14(9), 3446-3485 (2009).
82. Chong ZZ, Shang YC, Wang S, Maiese K. SIRT1: New avenues of discovery for disorders of oxidative stress. Expert Opin. Ther. Targets 16(2), 167-178 (2012).
83. Troy CM, Akpan N, Jean YY. Regulation of caspases in the nervous system implications for functions in health and disease. Prog. Mol. Biol. Transl. Sci. 99, 265-305 (2011).
84. Maiese K, Chong ZZ, Shang YC. OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins. Trends Mol. Med. 14(5), 219-227 (2008).
85. Chong ZZ, Li F, Maiese K. Oxidative stress in the brain: Novel cellular targets that govern survival during neurodegenerative disease. Prog. Neurobiol. 75(3), 207-246 (2005). (Pubitemid 40693131)
86. Maiese K, Chong ZZ, Shang YC, Wang S. Translating cell survival and cell longevity into treatment strategies with SIRT1. Rom. J. Morphol. Embryol. 52(4), 1173-1185 (2011).
87. Wang S, Chong ZZ, Shang YC, Maiese K. Wnt1 inducible signaling pathway protein 1 (WISP1) blocks neurodegeneration through phosphoinositide 3 kinase/Akt1 and apoptotic mitochondrial signaling involving Bad, Bax, Bim, and Bcl-xL. Curr. Neurovasc. Res. 9(1), 20-31 (2012).
88. Hou J, Wang S, Shang YC, Chong ZZ, Maiese K. Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress. Curr. Neurovasc. Res. 8(3), 220-235 (2011).
89. Koh PO. Nicotinamide attenuates the ischemic brain injury-induced decrease of Akt activation and Bad phosphorylation. Neurosci. Lett. 498(2), 105-109 (2011).
90. Dormond O, Madsen JC, Briscoe DM. The effects of mTOR-Akt interactions on anti-apoptotic signaling in vascular endothelial cells. J. Biol. Chem. 282(32), 23679-23686 (2007). (Pubitemid 47311969)
91. Chong ZZ, Hou J, Shang YC, Wang S, Maiese K. EPO relies upon novel signaling of wnt1 that requires Akt1, Foxo3a, GSK-3beta, and beta-catenin to foster vascular integrity during experimental diabetes. Curr. Neurovasc. Res. 8(2), 103-120 (2011).
92. Chong ZZ, Li F, Maiese K. The pro-survival pathways of mTOR and protein kinase B target glycogen synthase kinase-3beta and nuclear factor-kappaB to foster endogenous microglial cell protection. Int. J. Mol. Med. 19(2), 263-272 (2007).
93. Shang YC, Chong ZZ, Wang S, Maiese K. Prevention of beta-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL. Aging (Albany NY) 4(3), 187-201 (2012).
94. Choi KC, Kim SH, Ha JY, Kim ST, Son JH. A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death. J. Neurochem. 112(2), 366-376 (2010).
95. Chong ZZ, Shang YC, Wang S, Maiese K. PRAS40 is an integral regulatory component of erythropoietin mTOR signaling and cytoprotection. PLoS ONE 7(9), e45456 (2012).
96. Shang YC, Chong ZZ, Wang S, Maiese K. wnt1 inducible signaling pathway protein 1 (WISP1) targets PRAS40 to govern beta-amyloid apoptotic injury of microglia. Curr. Neurovasc. Res. (2012).
97. Thedieck K, Polak P, Kim ML et al. PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS ONE 2(11), e1217 (2007).
98. Pastor MD, Garcia-Yebenes I, Fradejas N et al. mTOR/S6 kinase pathway contributes to astrocyte survival during ischemia. J. Biol. Chem. 284(33), 22067-22078 (2009).
99. Wu X, Reiter CE, Antonetti DA, Kimball SR, Jefferson LS, Gardner T W. Insulin promotes rat retinal neuronal cell survival in a p70S6K-dependent manner. J. Biol. Chem. 279(10), 9167-9175 (2004). (Pubitemid 38295980)
100. Maiese K, Chong ZZ, Shang YC. Raves and risks for erythropoietin. Cytokine Growth Factor Rev. 19(2), 145-155 (2008).
101. Kim J, Jung Y, Sun H et al. Erythropoietin mediated bone formation is regulated by mTOR signaling. J. Cell Biochem. 113(1), 220-228 (2012).
102. Shang YC, Chong ZZ, Wang S, Maiese K. Erythropoietin and Wnt1 govern pathways of mTOR, Apaf-1, and XIAP in infammatory microglia. Curr. Neurovasc. Res. 8(4), 270-285 (2011).
103. Chong ZZ, Li F, Maiese K. Attempted cell cycle induction in post-mitotic neurons occurs in early and late apoptotic programs through Rb, E2f1, and caspase 3. Curr. Neurovasc. Res. 3(1), 25-39 (2006).
104. Yu Y, Ren QG, Zhang ZH et al. Phospho-Rb mediating cell cycle reentry induces early apoptosis following oxygen-glucose deprivation in rat cortical neurons. Neurochem. Res. 37(3), 503-511 (2012).
105. Bhaskar K, Miller M, Chludzinski A, Herrup K, Zagorski M, Lamb BT. The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events. Mol. Neurodegener. 4, 14 (2009).
106. Baryawno N, Sveinbjornsson B, Eksborg S, Chen CS, Kogner P, Johnsen JI. Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. Cancer Res. 70(1), 266-276 (2010).
107. Chung CY, Park YL, Song YA et al. Knockdown of RON inhibits AP-1 activity and induces apoptosis and cell cycle arrest through the modulation of Akt/FoxO signaling in human colorectal cancer cells. Dig. Dis. Sci. 57(2), 371-380 (2012).
108. Fokas E, Yoshimura M, Prevo R et al. NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity. Radiat. Oncol. 7(1), 48 (2012).
109. Janku F, Wheler JJ, Westin SN et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J. Clin. Oncol. 30(8), 777-782 (2012).
110. Yamada E, Singh R. Mapping autophagy on to your metabolic radar. Diabetes 61(2), 272-280 (2012).
111. Clarke PG. Developmental cell death: morphological diversity and multiple mechanisms. Anat. Embryol. 181(3), 195-213 (1990). (Pubitemid 20153523)
112. Levine B. Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120(2), 159-162 (2005). (Pubitemid 40174758)
113. Silva DF, Esteves AR, Oliveira CR, Cardoso SM. Mitochondria: the common upstream driver of amyloid-beta and tau pathology in Alzheimer's disease. Curr. Alzheimer Res. 8(5), 563-572 (2011).
114. Kapoor V, Zaharieva MM, Das SN, Berger MR. Erufosine simultaneously induces apoptosis and autophagy by modulating the Akt-mTOR signaling pathway in oral squamous cell carcinoma. Cancer Lett. 319(1), 39-48 (2012).
115. Le XF, Mao W, Lu Z, Carter BZ, Bast RC Jr. Dasatinib induces autophagic cell death in human ovarian cancer. Cancer 116(21), 4980-4990 (2010).
116. Viola G, Bortolozzi R, Hamel E et al. MG-2477, a new tubulin inhibitor, induces autophagy through inhibition of the Akt/mTOR pathway and delayed apoptosis in A549 cells. Biochem. Pharmacol. 83(1), 16-26 (2012).
117. Wu YT, Tan HL, Huang Q, Ong CN, Shen HM. Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy. Autophagy 5(6), 824-834 (2009).
118. Yu L, Mcphee CK, Zheng L et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465(7300), 942-946 (2010).
119. Rong Y, McPhee CK, Deng S et al. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. Proc. Natl Acad. Sci. USA 108(19), 7826-7831 (2011).
120. Jung CH, Jun CB, Ro SH et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20(7), 1992-2003 (2009).
121. Sarkar S, Ravikumar B, Rubinsztein DC. Autophagic clearance of aggregate-prone proteins associated with neurodegeneration. Methods Enzymol. 453, 83-110 (2009).
122. Berger Z, Ravikumar B, Menzies FM et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15(3), 433-442 (2006). (Pubitemid 43159895)
123. Ravikumar B, Vacher C, Berger Z et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fy and mouse models of Huntington disease. Nat. Genet. 36(6), 585-595 (2004). (Pubitemid 38715985)
124. Floto RA, Sarkar S, Perlstein EO, Kampmann B, Schreiber SL, Rubinsztein DC. Small molecule enhancers of rapamycin-induced TOR inhibition promote autophagy, reduce toxicity in Huntington's disease models and enhance killing of mycobacteria by macrophages. Autophagy 3(6), 620-622 (2007). (Pubitemid 350060063)
125. Roscic A, Baldo B, Crochemore C, Marcellin D, Paganetti P. Induction of autophagy with catalytic mTOR inhibitors reduces huntingtin aggregates in a neuronal cell model. J. Neurochem. 119(2), 398-407 (2011).
126. Fox JH, Connor T, Chopra V et al. The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease. Mol. Neurodegeneration 5, 26 (2010).
127. Hyrskyluoto A, Reijonen S, Kivinen J, Lindholm D, Korhonen L. GADD34 mediates cytoprotective autophagy in mutant huntingtin expressing cells via the mTOR pathway. Exp. Cell Res. 318(1), 33-42 (2012).
128. Maiese K, Chong ZZ, Hou J, Shang YC. New strategies for Alzheimer's disease and cognitive impairment. Oxid. Med. Cell Longev. 2(5), 279-289 (2009).
129. Slipczuk L, Bekinschtein P, Katche C, Cammarota M, Izquierdo I, Medina JH. BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS ONE 4(6), e6007 (2009).
130. Griffn RJ, Moloney A, Kelliher M et al. Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology. J. Neurochem. 93(1), 105-117 (2005). (Pubitemid 40463520)
131. An WL, Cowburn RF, Li L et al. Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofbrillary pathology in Alzheimer's disease. Am. J. Pathol. 163(2), 591-607 (2003). (Pubitemid 36909421)
132. Paccalin M, Pain-Barc S, Pluchon C et al. Activated mTOR and PKR kinases in lymphocytes correlate with memory and cognitive decline in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 22(4), 320-326 (2006). (Pubitemid 44651446)
133. Ma T, Hoeffer CA, Capetillo-Zarate E et al. Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease. PLoS ONE 5(9), e12845 (2010).
134. Lee ST, Chu K, Park JE et al. Erythropoietin improves memory function with reducing endothelial dysfunction and amyloid-beta burden in Alzheimer's disease models. J. Neurochem. 120(1), 115-124 (2012).
135. Lafay-Chebassier C, Paccalin M, Page G et al. mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease. J. Neurochem. 94(1), 215-225 (2005). (Pubitemid 40911407)
136. Chano T, Okabe H, Hulette CM. RB1CC1 insuffciency causes neuronal atrophy through mTOR signaling alteration and involved in the pathology of Alzheimer's diseases. Brain Res. 1168, 97-105 (2007). (Pubitemid 47320633)
137. Malagelada C, Ryu EJ, Biswas SC, Jackson-Lewis V, Greene LA. RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation. J. Neurosci. 26(39), 9996-10005 (2006). (Pubitemid 44477161)
138. Deyoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-13-3 shuttling. Genes Dev. 22(2), 239-251 (2008).
139. Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease. J. Neurosci. 30 (3), 1166-1175 (2010).
140. Imai Y, Gehrke S, Wang HQ et al. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. Embo J. 27(18), 2432-2443 (2008).
141. Tain LS, Mortiboys H, Tao RN, Ziviani E, Bandmann O, Whitworth AJ. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat. Neurosci. 12(9), 1129-1135 (2009).
142. Santini E, Heiman M, Greengard P, Valjent E, Fisone G. Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA-induced dyskinesia. Sci. Signal. 2(80), ra36 (2009).
143. Crews L, Spencer B, Desplats P et al. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS ONE 5(2), e9313 (2010).
144. Holmes GL, Stafstrom CE. Tuberous sclerosis complex and epilepsy: recent developments and future challenges. Epilepsia 48(4), 617-630 (2007). (Pubitemid 46587608)
145. Waltereit R, Welzl H, Dichgans J, Lipp HP, Schmidt WJ, Weller M. Enhanced episodic-like memory and kindling epilepsy in a rat model of tuberous sclerosis. J. Neurochem. 96(2), 407-413 (2006).
146. Zeng LH, Xu L, Gutmann DH, Wong M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol. 63(4), 444-453 (2008). (Pubitemid 351614710)
147. Zeng LH, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J. Neurosci. 29(21), 6964-6972 (2009).
148. Buckmaster PS, Ingram EA, Wen X. Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J. Neurosci. 29(25), 8259-8269 (2009).
149. Balduini W, Carloni S, Buonocore G. Autophagy in hypoxia-ischemia induced brain inju r y. J. Matern. Fetal Neonatal Med. 25(Suppl. 1), 30-34 (2012).
150. Shi GD, Ouyang Y P, Shi JG, Liu Y, Yuan W, Jia LS. PTEN deletion prevents ischemic brain injury by activating the mTOR signaling pathway. Biochem. Biophys. Res. Commun. 404(4), 941-945 (2011).
151. Zhang W, Khatibi NH, Yamaguchi-Okada M et al. Mammalian target of rapamycin (mTOR) inhibition reduces cerebral vasospasm following a subarachnoid hemorrhage injury in canines. Exp. Neurol. 233(2), 799-806 (2012).
152. Erlich S, Alexandrovich A, Shohami E, Pinkas-Kramarski R. Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol. Dis. 26(1), 86-93 (2007). (Pubitemid 46436489)
153. Sekiguchi A, Kanno H, Ozawa H, Yamaya S, Itoi E. Rapamycin promotes autophagy and reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. J. Neurotrauma 29(5), 946-956 (2012).
154. Sheng B, Liu J, Li GH. Metformin preconditioning protects Daphnia pulex from lethal hypoxic insult involving AMPK, HIF and mTOR signaling. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 163(1), 51-58 (2012).
155. Koh PO. Melatonin prevents ischemic brain injury through activation of the mTOR/p70S6 kinase signaling pathway. Neurosci. Lett. 444(1), 74-78 (2008).
156. Liu G, Detloff MR, Miller KN, Santi L, Houle JD. Exercise modulates microRNAs that affect the PTEN/mTOR pathway in rats after spinal cord injury. Exp. Neurol. 233(1), 447-456 (2012).
157. Sun F, Park KK, Belin S et al. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 480(7377), 372-375 (2011).
158. Liu K, Lu Y, Lee JK et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13(9), 1075-1081 (2010).
159. Park KK, Liu K, Hu Y et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322(5903), 963-966 (2008).
160. Hu LY, Sun ZG, Wen YM et al. ATP-mediated protein kinase B Akt/mammalian target of rapamycin mTOR/p70 ribosomal S6 protein p70S6 kinase signaling pathway activation promotes improvement of locomotor function after spinal cord injury in rats. Neuroscience 169(3), 1046-1062 (2010).
161. Walker CL, Walker MJ, Liu NK et al. Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy, and enhances recovery following cervical spinal cord injury. PLoS ONE 7(1), e30012 (2012).
162. Pavel ME, Hainsworth JD, Baudin E et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, Phase 3 study. Lancet 378(9808), 2005-2012 (2011).
163. Barrett D, Brown VI, Grupp SA, Teachey DT. Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr. Drugs 14(5), 299-316 (2012).
164. Grzybowska-Izydorczyk O, Smolewski P. mTOR kinase inhibitors as a treatment strategy in hematological malignancies. Future Med. Chem. 4(4), 487-504 (2012).
165. Hernandez G, Lal H, Fidalgo M et al. A novel cardioprotective p38-MAPK/mTOR pathway. Exp. Cell Res. 317(20), 2938-2949 (2011).
166. Sinha SS, Pham MX, Vagelos RH et al. Effect of rapamycin therapy on coronary artery physiology early after cardiac transplantation. Am. Heart J. 155(5), 889.e1-6 (2008).