Increased 90-kDa ribosomal S6 kinase (Rsk) activity is protective against mutant huntingtin toxicity

Springer Science and Business Media LLC - 2011
Xavier Xifró1, Marta Anglada-Huguet1, Laura Rué1, Ana Saavedra1, Esther Pérez‐Navarro1, Jordi Alberch1
1Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Spain

Tóm tắt

Abstract Background The 90-kDa ribosomal S6 kinase (Rsk) family is involved in cell survival. Rsk activation is regulated by sequential phosphorylations controlled by extracellular signal-regulated kinase (ERK) 1/2 and 3-phosphoinositide-dependent protein kinase 1 (PDK1). Altered ERK1/2 and PDK1 phosphorylation have been described in Huntington's disease (HD), characterized by the expression of mutant huntingtin (mhtt) and striatal degeneration. However, the role of Rsk in this neurodegenerative disease remains unknown. Here, we analyzed the protein levels, activity and role of Rsk in in vivo and in vitro HD models. Results We observed increased protein levels of Rsk1 and Rsk2 in the striatum of HdhQ111/Q111 and R6/1 mice, STHdhQ111/Q111 cells and striatal cells transfected with full-length mhtt. Analysis of the phosphorylation of Rsk in Hdh mice and STHdh cells showed reduced levels of phospho Ser-380 (dependent on ERK1/2), whereas phosphorylation at Ser-221 (dependent on PDK1) was increased. Moreover, we found that elevated Rsk activity in STHdhQ111/Q111 cells was mainly due to PDK1 activity, as assessed by transfection with Rsk mutant constructs. The increase of Rsk in STHdhQ111/Q111 cells occurred in the cytosol and in the nucleus, which results in enhanced phosphorylation of both cytosolic and nuclear Rsk targets. Finally, pharmacological inhibition of Rsk, knock-down and overexpression experiments indicated that Rsk activity exerts a protective effect against mhtt-induced cell death in STHdhQ7/Q7 cells transfected with mhtt. Conclusion The increase of Rsk levels and activity would act as a compensatory mechanism with capacity to prevent mhtt-mediated cell death. We propose Rsk as a good target for neuroprotective therapies in HD.

Từ khóa


Tài liệu tham khảo

Anjum R, Blenis J: The RSK family of kinases: emerging roles in cellular signaling. Nat Rev Mol Cell Biol. 2008, 9: 747-758. 10.1038/nrm2509.

Chen RH, Sarnecki C, Blenis J: Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol. 1992, 12: 915-927.

Jensen CJ, Buch MB, Krag TO, Hemmings BA, Gammeltoft S, Frödin M: 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. J Biol Chem. 1999, 274: 27168-27176. 10.1074/jbc.274.38.27168.

Frödin M, Gammeltoft S: Role and regulation of 90-kDa ribosomal S6 kinase (RSK) in signal transduction. Mol Cell Endocrinol. 1999, 151: 65-77. 10.1016/S0303-7207(99)00061-1.

Tan Y, Ruan H, Demeter MR, Comb MJ: p90(RSK) blocks bad-mediated cell death via a protein kinase C-dependent pathway. J Biol Chem. 1999, 274: 34859-34867. 10.1074/jbc.274.49.34859.

Sutherland C, Leighton IA, Cohen P: Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J. 1993, 296: 15-19.

Anjum R, Roux PP, Ballif BA, Gygi SP, Blenis J: The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling. Curr Biol. 2005, 15: 1762-1767. 10.1016/j.cub.2005.08.050.

Xing J, Ginty DD, Greenberg ME: Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science. 1996, 273: 959-963. 10.1126/science.273.5277.959.

Rivera VM, Miranti CK, Misra RP, Ginty DD, Chen RH, Blenis J, Greenberg ME: A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity. Mol Cell Biol. 1993, 13: 6260-6273.

Ghoda L, Lin X, Greene WC: The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of IkappaB alpha and stimulates its degradation in vitro. J Biol Chem. 1997, 272: 21281-21288. 10.1074/jbc.272.34.21281.

Schouten GJ, Vertegaal AC, Whiteside ST, Israël A, Toebes M, Dorsman JC, van der EB AJ, Zantema A: IkappaB alpha is a target for the mitogen-activated 90 kDa ribosomal S6 kinase. EMBO J. 1997, 16: 3133-3144. 10.1093/emboj/16.11.3133.

Ginty DD, Bonni A, Greenberg ME: Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell. 1994, 77: 713-725. 10.1016/0092-8674(94)90055-8.

Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME: Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science. 1999, 286: 1358-1362. 10.1126/science.286.5443.1358.

Kharebava G, Makonchuk D, Kalita KB, Zheng JJ, Hetman M: Requirement of 3-phosphoinositide-dependent protein kinase-1 for BDNF-mediated neuronal survival. J Neurosci. 2008, 28: 11409-11420. 10.1523/JNEUROSCI.2135-08.2008.

The Huntington's disease collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993, 72: 971-983. 10.1016/0092-8674(93)90585-E.

Reiner A, Albin RL, Anderson KD, D'Amato CJ, Penney JB, Young AB: Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci USA. 1998, 85: 5733-5737.

Gines S, Ivanova E, Seong IS, Saura CA, MacDonald ME: Enhanced Akt signaling is an early pro-survival response that reflects N-methyl-D-aspartate receptor activation in Huntington's disease knock-in striatal cells. J Biol Chem. 2003, 278: 50514-50522. 10.1074/jbc.M309348200.

Gines S, Paoletti P, Alberch J: Impaired TrkB-mediated ERK1/2 activation in huntington disease knock-in striatal cells involves reduced p52/p46 Shc expression. J Biol Chem. 2010, 285: 21537-21548. 10.1074/jbc.M109.084202.

Maher P, Dargusch R, Bodai L, Gerard PE, Purcell JM, Marsh JL: ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. Hum Molec Genet. 2011, 20: 261-270. 10.1093/hmg/ddq460.

Scotter EL, Goodfellow CE, Graham ES, Dragunow M, Glass M: Neuroprotective potential of CB1 receptor agonists in an in vitro model of Huntington's disease. Br J Pharmacol. 2010, 160: 747-761. 10.1111/j.1476-5381.2010.00773.x.

Apostol BL, Illes K, Pallos J, Bodai L, Wu J, Strand A, Schweitzer ES, Olson JM, Kazantsev A, Marsh JL, Thompson LM: Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum Molec Genet. 2006, 15: 273-285.

Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP: Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996, 87: 493-506. 10.1016/S0092-8674(00)81369-0.

Sapkota GP, Cummings L, Newell FS, Armstrong C, Bain J, Frodin M, Grauert M, Hoffmann M, Schnapp G, Steegmaier L, Cohen P, Alessi DR: BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. Biochem J. 2007, 401: 29-38. 10.1042/BJ20061088.

Menalled LB: Knock-in mouse models of Huntington's disease. NeuroRx. 2005, 2: 465-470. 10.1602/neurorx.2.3.465.

Wheeler VC, Auerbach W, White JK, Srinidhi J, Auerbach A, Ryan A, Duyao MA, Vrbanac V, Weaver M, Gusella JF, Joyner AL, MacDonald ME: Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Hum Molec Genet. 1999, 8: 115-122. 10.1093/hmg/8.1.115.

Fossale E, Wheeler WC, Vrbanac V, Lebel LA, Teed A, Mysore JS, Gusella JF, MacDonald ME, Persichetti E: Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice. Hum Molec Genet. 2002, 11: 2233-2241. 10.1093/hmg/11.19.2233.

Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT: Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat Neurosci. 2002, 5: 731-736.

Perez-Navarro E, Canals JM, Gines S, Alberch J: Cellular and molecular mechanisms involved in the selective vulnerability of striatal projection neurons in Huntington's disease. Histol Histopathol. 2006, 21: 1217-1232.

Trettel F, Rigamonti D, Hilditch-Maguire P, Wheller VC, Sharp AH, Persichetti F, Cattaneo E, MacDonald ME: Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum Molec Genet. 2000, 9: 2799-2809. 10.1093/hmg/9.19.2799.

Humbert S, Bryson EA, Cordelières FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F: The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev Cell. 2002, 2: 831-837. 10.1016/S1534-5807(02)00188-0.

Saavedra A, García-Mártinez JM, Xifró X, Giralt A, Torres-Peraza JF, Canals JM, Díaz-Hernandez M, Lucas JJ, Alberch J, Pérez-Navarro E: PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum. Cell Death Differ. 2010, 17: 324-335. 10.1038/cdd.2009.127.

Rangone H, Poizat G, Troncoso J, Ross CA, MacDonald ME, Saudou F, Humbert S: The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. Eur J Neurosci. 2004, 19: 273-279. 10.1111/j.0953-816X.2003.03131.x.

Choen MS, Hadjivassiliou H, Taunton J: A clickable inhibitor reveals context-dependent autoactivation of p90 RSK. Nat Chem Biol. 2007, 3: 156-160. 10.1038/nchembio859.

Williams MR, Arthur JS, Balendran A, van der Kaay J, Poli V, Cohen P, Alessi DR: The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells. Curr Biol. 2000, 10: 439-448. 10.1016/S0960-9822(00)00441-3.

Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E: Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science. 2001, 293: 445-446. 10.1126/science.1063429.

Zuccato C, Cattaneo E: Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol. 2009, 5: 311-322. 10.1038/nrneurol.2009.54.

De Cesare D, Jacquot S, Hanauer A, Sassone-Corsi P: Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene. Proc Natl Acad Sci USA. 1998, 95: 12202-12207. 10.1073/pnas.95.21.12202.

Giralt A, Rodrigo TM, Martin ED, Gonzalez JR, Mila M, Ceña V, Dierssen M, Canals JM, Alberch J: Brain-derived neurotrophic factor modulates the severity of cognitive alterations induced by mutant huntingtin: involvement of phospholipaseCgamma activity and glutamate receptor expression. Neuroscience. 2009, 158: 1234-1250. 10.1016/j.neuroscience.2008.11.024.

Giordano M, Takashima H, Herranz A, Polotorak M, Geller HM, Marone M, Freed WJ: Immortalized GABAergic cell lines derived from rat striatum using a temperature-sensitive allele of the SV40 large T antigen. Exp Neurol. 1993, 124: 395-400. 10.1006/exnr.1993.1213.

Gratacos E, Checa N, Perez-Navarro E, Alberch J: Brain-derived neurotrophic factor (BDNF) mediates bone morphogenetic protein-2 (BMP-2) effects on cultured striatal neurones. J Neurochem. 2001, 79: 747-755.

Xifro X, Garcia-Martinez JM, del Toro D, Alberch J, Perez-Navarro E: Calcineurin is involved in the early activation of NMDA-mediated cell death in mutant huntingtin knock-in striatal cells. J Neurochem. 2008, 105: 1596-1612. 10.1111/j.1471-4159.2008.05252.x.

Del Toro D, Canals JM, Gines S, Kojima M, Egea G, Alberch J: Mutant huntingtin impairs the post-Golgi trafficking of brain-derived neurotrophic factor but not its Val66Met polymorphism. J Neurosci. 2006, 26: 12748-12757. 10.1523/JNEUROSCI.3873-06.2006.

Sapkota GP, Kieloch A, Lizcano JM, Lain S, Arthur JS, Williams MR, Morrice N, Deak M, Alessi DR: Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth. J Biol Chem. 2001, 276: 19469-19482. 10.1074/jbc.M009953200.

Thông tin
Thông tin xuất bản

Springer Science and Business Media LLC

Thông tin tác giả