The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord

Journal of Neuroscience

Volumn 29, Issue 4, 2009, Pages 1093-1104

  Codeluppi, Simone ^a,b   Svensson, Camilla I ^c   Hefferan, Michael P ^c   Valencia, Fatima ^a   Silldorff, Morgan D ^a   Oshiro, Masakatsu ^c,e   Marsala, Martin ^c,d   Pasquale, Elena B ^a,b  

^a BURNHAM INSTITUTE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c University of California   (United States)

^d INSTITUTE OF CHEMISTRY   (Slovakia)

^e UNIVERSITY OF THE RYUKYUS   (Japan)

Author keywords

Akt; Cell migration; Ischemia; Rapamycin; Spinal cord injury; Tuberin

Indexed keywords

EPIDERMAL GROWTH FACTOR RECEPTOR; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; RAPAMYCIN; RAS PROTEIN; RHEB PROTEIN; TUBERIN;

ANIMAL CELL; ARTICLE; ASTROCYTE; CELL TRANSFORMATION; GLIOSIS; ISCHEMIA; NERVE FIBER REGENERATION; NONHUMAN; OPTIC NERVE INJURY; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RAT; SPINAL CORD INJURY;

ANALYSIS OF VARIANCE; ANIMALS; ASTROCYTES; CELLS, CULTURED; CHROMONES; DISEASE MODELS, ANIMAL; ENZYME INHIBITORS; EPIDERMAL GROWTH FACTOR; EXCITATORY AMINO ACID TRANSPORTER 2; FLAVONOIDS; GLIAL FIBRILLARY ACIDIC PROTEIN; IMMUNOSUPPRESSIVE AGENTS; MALE; MONOMERIC GTP-BINDING PROTEINS; MORPHOLINES; NEUROPEPTIDES; PROTEIN KINASES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, EPIDERMAL GROWTH FACTOR; RNA, MESSENGER; SIGNAL TRANSDUCTION; SIROLIMUS; SPINAL CORD INJURIES; TRANSCRIPTION FACTORS; TRANSFECTION; UP-REGULATION; VIMENTIN;

EID: 59649110910     PISSN: 02706474     EISSN: 02706474     Source Type: Journal    
DOI: 10.1523/JNEUROSCI.4103-08.2009     Document Type: Article

References (64)

1. Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, Jiang Y (2007) Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318:977-980.
2. Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JSC, Alessi DR, Cohen P (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J 408:297-315.
3. Berven LA, Willard FS, Crouch MF (2004) Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration. Exp Cell Res 296:183-195.
4. Bhaskar PT, Hay N (2007) The two TORCs and Akt. Dev Cell 12:487-502.
5. Bochelen D, Rudin M, Sauter A (1999) Calcineurin inhibitors FK506 and SDZ ASM 981 alleviate the outcome of focal cerebral ischemic/reperfusion injury. J Pharmacol Exp Ther 288:653-659.
6. Boyle DL, Rosengren S, Bugbee W, Kavanaugh A, Firestein GS (2003) Quantitative biomarker analysis of synovial gene expression by real-time PCR. Arthritis Res Ther 5:R352-R360.
7. Busch SA, Silver J (2007) The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol 17:120-127.
8. Castro AF, Rebhun JF, Clark GJ, Quilliam LA (2003) Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin-and farnesylation-dependent manner. J Biol Chem 278:32493-32496.
9. Chiang GG, Abraham RT (2007) Targeting the mTOR signaling network in cancer. Trends Mol Med 13:433-442.
10. Choi YJ, Di Nardo A, Kramvis I, Meikle L, Kwiatkowski DJ, Sahin M, He X (2008) Tuberous sclerosis complex proteins control axon formation. Genes Dev 22:2485-2495.
11. Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505-516.
12. Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, et al. (2008) Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5:e8.
13. David G, Bai XM, Van der Schueren B, Cassiman JJ, Van den Berghe H (1992) Developmental changes in heparan sulfate expression: in situ detection with mAbs. J Cell Biol 119:961-975.
14. David S, Lacroix S (2003) Molecular approaches to spinal cord repair. Annu Rev Neurosci 26:411-440.
15. do Carmo Cunha J, de Freitas Azevedo Levy B, de Luca BA, de Andrade MS, Gomide VC, Chadi G (2007) Responses of reactive astrocytes containing S100beta protein and fibroblast growth factor-2 in the border and in the adjacent preserved tissue after a contusion injury of the spinal cord in rats: implications for wound repair and neuroregeneration. Wound Repair Regen 15:134-146.
16. Eddleston M, Mucke L (1993) Molecular profile of reactive astrocytes - implications for their role in neurologic disease. Neuroscience 54:15-36.
17. Erlich S, Alexandrovich A, Shohami E, Pinkas-Kramarski R (2007) Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol Dis 26:86-93.
18. Erschbamer M, Pernold K, Olson L (2007) Inhibiting epidermal growth factor receptor improves structural, locomotor, sensory, and bladder recovery from experimental spinal cord injury. J Neurosci 27:6428-6435.
19. Ess KC, Uhlmann EJ, Li W, Li H, Declue JE, Crino PB, Gutmann DH (2004) Expression profiling in tuberous sclerosis complex (TSC) knockout mouse astrocytes to characterize human TSC brain pathology. Glia 46:28-40.
20. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143-2155.
21. Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G, Dinopoulos A, Thomas G, Crone KR (2006) Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59:490-498.
22. Fraser MM, Zhu X, Kwon C-H, Uhlmann EJ, Gutmann DH, Baker SJ (2004) Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo. Cancer Res 64:7773-7779.
23. Frisén J, Johansson CB, Török C, Risling M, Lendahl U (1995) Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS injury. J Cell Biol 131:453-464.
24. Hefferan MP, Kucharova K, Kinjo K, Kakinohana O, Sekerkova G, Nakamura S, Fuchigami T, Tomori Z, Yaksh TL, Kurtz N, Marsala M (2007) Spinal astrocyte glutamate receptor 1 overexpression after ischemic insult facilitates behavioral signs of spasticity and rigidity. J Neurosci 27:11179-11191.
25. Im E, von Lintig FC, Chen J, Zhuang S, Qui W, Chowdhury S, Worley PF, Boss GR, Pilz RB (2002) Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene 21:6356-6365.
26. Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, Natesan S, Brugge JS (2005) Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol 171:1023-1034.
27. Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122-1128.
28. Junier MP (2000) What role(s) for TGFalpha in the central nervous system? Prog Neurobiol 62:443-473.
29. Kobayashi T, Hino S, Oue N, Asahara T, Zollo M, Yasui W, Kikuchi A (2006) Glycogen synthase kinase 3 and h-prune regulate cell migration by modulating focal adhesions. Mol Cell Biol 26:898-911.
30. Koprivica V, Cho KS, Park JB, Yiu G, Atwal J, Gore B, Kim JA, Lin E, Tessier-Lavigne M, Chen DF, He Z (2005) EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science 310:106-110.
31. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943-1947.
32. Liu B, Neufeld AH (2007) Activation of epidermal growth factor receptors in astrocytes: from development to neural injury. J Neurosci Res 85:3523-3529.
33. Liu B, Chen H, Johns TG, Neufeld AH (2006) Epidermal growth factor receptor activation: an upstream signal for transition of quiescent astrocytes into reactive astrocytes after neural injury. J Neurosci 26:7532-7540.
34. Liu H, Radisky DC, Nelson CM, Zhang H, Fata JE, Roth RA, Bissell MJ (2006) Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. Proc Natl Acad Sci U S A 103:4134-4139.
35. Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC (2006) Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell 21:521-531.
36. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261-1274.
37. Marsala M, Kakinohana O, Yaksh TL, Tomori Z, Marsala S, Cizkova D (2004) Spinal implantation of hNT neurons and neuronal precursors: graft survival and functional effects in rats with ischemic spastic paraplegia. Eur J Neurosci 20:2401-2414.
38. Menet V, Prieto M, Privat A, Giménez y Ribotta M (2003) Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proc Natl Acad Sci U S A 100:8999-9004.
39. O'Reilly KE, Rojo F, She Q-B, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500-1508.
40. Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, Xu B, Connolly L, Kramvis I, Sahin M, He Z (2008) Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322:963-966.
41. Pekny M, Johansson CB, Eliasson C, Stakeberg J, Wallén A, Perlmann T, Lendahl U, Betsholtz C, Berthold CH, Frisén J (1999) Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J Cell Biol 145:503-514.
42. Properzi F, Fawcett JW (2004) Proteoglycans and brain repair. News Physiol Sci 19:33-38.
43. Properzi F, Lin R, Kwok J, Naidu M, van Kuppevelt TH, Ten Dam GB, Camargo LM, Raha-Chowdhury R, Furukawa Y, Mikami T, Sugahara K, Fawcett JW (2008) Heparan sulphate proteoglycans in glia and in the normal and injured CNS: expression of sulphotransferases and changes in sulphation. Eur J Neurosci 27:593-604.
44. Qian Y, Corum L, Meng Q, Blenis J, Zheng JZ, Shi X, Flynn DC, Jiang B-H (2004) PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration. Am J Physiol Cell Physiol 286:C153-C163.
45. Qiu Q, Yang M, Tsang BK, Gruslin A (2004) Both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signalling are required in epidermal growth factor-induced human trophoblast migration. Mol Hum Reprod 10:677-684.
46. Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570-577.
47. Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6:729-734.
48. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296-1302.
49. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098-1101.
50. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159-168.
51. Sharkey J, Butcher SP (1994) Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature 371:336-339.
52. Shaw RJ, Cantley LC (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441:424-430.
53. Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146-156.
54. Smith GM, Strunz C (2005) Growth factor and cytokine regulation of chondroitin sulfate proteoglycans by astrocytes. Glia 52:209-218.
55. Stambolic V, Woodgett JR (2006) Functional distinctions of protein kinase B/Akt isoforms defined by their influence on cell migration. Trends Cell Biol 16:461-466.
56. Tachibana T, Shiiya N, Kunihara T, Wakamatsu Y, Kudo AF, Ooka T, Watanabe S, Yasuda K (2005) Immunophilin ligands FK506 and cyclosporine A improve neurologic and histopathologic outcome after transient spinal cord ischemia in rabbits. J Thorac Cardiovasc Surg 129:123-128.
57. Taira Y, Marsala M (1996) Effect of proximal arterial perfusion pressure on function, spinal cord blood flow, and histopathologic changes after increasing intervals of aortic occlusion in the rat. Stroke 27:1850-1858.
58. Tawfik VL, Lacroix-Fralish ML, Bercury KK, Nutile-McMenemy N, Harris BT, Deleo JA (2006) Induction of astrocyte differentiation by propentofylline increases glutamate transporter expression in vitro: heterogeneity of the quiescent phenotype. Glia 54:193-203.
59. Uhlmann EJ, Li W, Scheidenhelm DK, Gau CL, Tamanoi F, Gutmann DH (2004) Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased Rheb/S6K pathway signaling important for astrocyte cell size regulation. Glia 47:180-188.
60. Wang MY, Lu KV, Zhu S, Dia EQ, Vivanco I, Shackleford GM, Cavenee WK, Mellinghoff IK, Cloughesy TF, Sawyers CL, Mischel PS (2006) Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res 66:7864-7869.
61. Wu EHT, Wu KKH, Wong YH (2007) Tuberin: a stimulus-regulated tumor suppressor protein controlled by a diverse array of receptor tyrosine kinases and G protein-coupled receptors. Neurosignals 15:217-227.
62. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471-484.
63. Yiu G, He Z (2006) Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7:617-627.
64. Zhou X, Zhu J, Liu KY, Sabatini BL, Wong STC (2006) Mutual information-based feature selection in studying perturbation of dendritic structure caused by TSC2 inactivation. Neuroinformatics 4:81-94.