Inducing autophagy a comparative phosphoproteomic study of the cellular response to ammonia and rapamycin

Autophagy

Volumn 10, Issue 2, 2014, Pages 339-355

  Harder, Lea M ^a   Bunkenborg, Jakob ^a   Andersen, Jens S ^a  

^a UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

Author keywords

Ammonia; Autophagy; MTOR; Phosphoproteomics; Rapamycin; Unfolded protein response

Indexed keywords

AMMONIA; CONCANAMYCIN A; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHOSPHOPROTEIN; PROLINE; RAPAMYCIN; SERINE; THREONINE;

ARTICLE; AUTOPHAGOSOME; AUTOPHAGY; CANCER CELL; CATABOLISM; CELL SURVIVAL; CONTROLLED STUDY; ENDOPLASMIC RETICULUM STRESS; HUMAN; HUMAN CELL; PROTEIN DEPHOSPHORYLATION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; STIMULATION; UNFOLDED PROTEIN RESPONSE; UPREGULATION;

AMMONIA; AUTOPHAGY; MTOR; PHOSPHOPROTEOMICS; RAPAMYCIN; UNFOLDED PROTEIN RESPONSE;

AMMONIA; AUTOPHAGY; CELL LINE, TUMOR; CELL SURVIVAL; HUMANS; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; PROTEOMICS; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 84894411492     PISSN: 15548627     EISSN: 15548635     Source Type: Journal    
DOI: 10.4161/auto.26863     Document Type: Article

References (91)

1. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43:67-93; PMID:19653858; http://dx.doi.org/10. 1146/annurev-genet-102808-114910
2. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132:27-42; PMID:18191218; http://dx.doi.org/10.1016/j.cell.2007.12.018
3. Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell 2010; 40:280-93; PMID:20965422; http://dx.doi.org/10.1016/j. molcel.2010.09.023
4. Neufeld TP. TOR-dependent control of autophagy: biting the hand that feeds. Curr Opin Cell Biol 2010; 22:157-68; PMID:20006481; http://dx.doi.org/10. 1016/j.ceb.2009.11.005
5. Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 1995; 270:2320-6; PMID:7836465; http://dx.doi.org/10.1074/jbc.270.5.2320
6. Szeliga M, Obara-Michlewska M. Glutamine in neoplastic cells: focus on the expression and roles of glutaminases. Neurochem Int 2009; 55:71-5; PMID:19428809; http://dx.doi.org/10.1016/j.neuint.2009.01.008
7. Eng CH, Yu K, Lucas J, White E, Abraham RT. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci Signal 2010; 3:ra31; PMID:20424262; http://dx.doi.org/10.1126/scisignal.2000911
8. Cheong H, Lindsten T, Wu J, Lu C, Thompson CB. Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc Natl Acad Sci U S A 2011; 108:11121-6; PMID:21690395; http://dx.doi.org/10.1073/pnas.1107969108
9. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994; 78:35-43; PMID:7518356; http://dx.doi.org/10.1016/0092-8674(94)90570-3
10. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M. Global, in vivo, and sitespecific phosphorylation dynamics in signaling networks. Cell 2006; 127:635-48; PMID:17081983; http://dx.doi.org/10.1016/j. cell.2006.09.026
11. Blom N, Gammeltoft S, Brunak S. Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol 1999; 294:1351-62; PMID:10600390; http://dx.doi.org/10.1006/jmbi.1999.3310
12. Schwartz D, Gygi SP. An iterative statistical approach to the identification of protein phosphorylation motifs from large-scale data sets. Nat Biotechnol 2005; 23:1391-8; PMID:16273072; http://dx.doi.org/10.1038/nbt1146
13. Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A, Eguchi S, Miyamoto T, Hara K, Takehana K, Avruch J, 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 2007; 282:20329-39; PMID:17517883; http://dx.doi.org/10. 1074/jbc.M702636200
14. Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, Birnbaum MJ, Roth RA. Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J Biol Chem 2003; 278:10189-94; PMID:12524439; http://dx.doi.org/10.1074/jbc. M210837200
15. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 2011; 332:1317-22; PMID:21659604; http://dx.doi.org/10.1126/science.1199498
16. Damoc E, Fraser CS, Zhou M, Videler H, Mayeur GL, Hershey JW, Doudna JA, Robinson CV, Leary JA. Structural characterization of the human eukaryotic initiation factor 3 protein complex by mass spectrometry. Mol Cell Proteomics 2007; 6:1135-46; PMID:17322308; http://dx.doi.org/10.1074/mcp.M600399-MCP200
17. Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD, Sonenberg N, Hershey JW. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J 2004; 23:1761-9; PMID:15071500; http://dx.doi.org/10.1038/sj.emboj.7600193
18. Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 2005; 123:569-80; PMID:16286006; http://dx.doi.org/10.1016/j.cell.2005.10.024
19. Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001; 15:807-26; PMID:11297505; http://dx.doi.org/10. 1101/gad.887201
20. Vary TC, Deiter G, Lynch CJ. Rapamycin limits formation of active eukaryotic initiation factor 4F complex following meal feeding in rat hearts. J Nutr 2007; 137:1857-62; PMID:17634255
21. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 2004; 166:213-23; PMID:15249583; http://dx.doi.org/10.1083/jcb.200403069
22. Palamarchuk A, Efanov A, Maximov V, Aqeilan RI, Croce CM, Pekarsky Y. Akt phosphorylates and regulates Pdcd4 tumor suppressor protein. Cancer Res 2005; 65:11282-6; PMID:16357133; http://dx.doi.org/10.1158/0008-5472.CAN-05-3469
23. Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M. S6K1-and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 2006; 314:467-71; PMID:17053147; http://dx.doi.org/10.1126/science.1130276
24. Didichenko SA, Fragoso CM, Thelen M. Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. J Biol Chem 2003; 278:26055-64; PMID:12719431; http://dx.doi.org/10.1074/jbc.M301657200
25. Krieg J, Hofsteenge J, Thomas G. Identification of the 40 S ribosomal protein S6 phosphorylation sites induced by cycloheximide. J Biol Chem 1988; 263:11473-7; PMID:3403539
26. 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 2007; 25:209-26; PMID:18092230; http://dx.doi.org/10.1080/08977190701779101
27. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110:163-75; PMID:12150925; http://dx.doi.org/10.1016/S0092-8674(02)00808-5
28. Peterson RT, Desai BN, Hardwick JS, Schreiber SL. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Proc Natl Acad Sci U S A 1999; 96:4438-42; PMID:10200280; http://dx.doi.org/10.1073/pnas.96.8.4438
29. Wang L, Lawrence JC Jr., Sturgill TW, Harris TE. Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR. J Biol Chem 2009; 284:14693-7; PMID:19346248; http://dx.doi.org/10.1074/jbc.C109.002907
30. Abraham RT, Eng CH. Mammalian target of rapamycin as a therapeutic target in oncology. Expert Opin Ther Targets 2008; 12:209-22; PMID:18208369; http://dx.doi.org/10.1517/14728222.12.2.209
31. Moritz A, Li Y, Guo A, Villén J, Wang Y, MacNeill J, Kornhauser J, Sprott K, Zhou J, Possemato A, et al. Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases. Sci Signal 2010; 3:ra64; PMID:20736484; http://dx.doi.org/10.1126/scisignal.2000998
32. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110:177-89; PMID:12150926; http://dx.doi.org/10. 1016/S0092-8674(02)00833-4
33. Linding R, Jensen LJ, Ostheimer GJ, van Vugt MA, Jørgensen C, Miron IM, Diella F, Colwill K, Taylor L, Elder K, et al. Systematic discovery of in vivo phosphorylation networks. Cell 2007; 129:1415-26; PMID:17570479; http://dx.doi.org/10.1016/j.cell.2007.05.052
34. Lekmine F, Uddin S, Sassano A, Parmar S, Brachmann SM, Majchrzak B, Sonenberg N, Hay N, Fish EN, Platanias LC. Activation of the p70 S6 kinase and phosphorylation of the 4E-BP1 repressor of mRNA translation by type I interferons. J Biol Chem 2003; 278:27772-80; PMID:12759354; http://dx.doi.org/ 10.1074/jbc.M301364200
35. Anderson NG, Maller JL, Tonks NK, Sturgill TW. Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase. Nature 1990; 343:651-3; PMID:2154696; http://dx.doi.org/10.1038/ 343651a0
36. Vanhatupa S, Ungureanu D, Paakkunainen M, Silvennoinen O. MAPK-induced Ser727 phosphorylation promotes SUMOylation of STAT1. Biochem J 2008; 409:179-85; PMID:17897103; http://dx.doi.org/10.1042/BJ20070620
37. Kelley LC, Hayes KE, Ammer AG, Martin KH, Weed SA. Cortactin phosphorylated by ERK1/2 localizes to sites of dynamic actin regulation and is required for carcinoma lamellipodia persistence. PLoS One 2010; 5:e13847; PMID:21079800; http://dx.doi.org/10.1371/journal.pone.0013847
38. Woo MS, Ohta Y, Rabinovitz I, Stossel TP, Blenis J. Ribosomal S6 kinase (RSK) regulates phosphorylation of filamin A on an important regulatory site. Mol Cell Biol 2004; 24:3025-35; PMID:15024089; http://dx.doi.org/10.1128/MCB.24. 7.3025-3035.2004
39. Takahashi E, Abe J, Gallis B, Aebersold R, Spring DJ, Krebs EG, Berk BC. p90(RSK) is a serumstimulated Na+/H+ exchanger isoform-1 kinase. Regulatory phosphorylation of serine 703 of Na+/H+ exchanger isoform-1. J Biol Chem 1999; 274:20206-14; PMID:10400637; http://dx.doi.org/10.1074/jbc.274.29.20206
40. Gille H, Kortenjann M, Thomae O, Moomaw C, Slaughter C, Cobb MH, Shaw PE. ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO J 1995; 14:951-62; PMID:7889942
41. Lin FT, Miller WE, Luttrell LM, Lefkowitz RJ. Feedback regulation of beta-arrestin1 function by extracellular signal-regulated kinases. J Biol Chem 1999; 274:15971-4; PMID:10347142; http://dx.doi.org/10.1074/jbc.274.23.15971
42. Lovrić J, Dammeier S, Kieser A, Mischak H, Kolch W. Activated raf induces the hyperphosphorylation of stathmin and the reorganization of the microtubule network. J Biol Chem 1998; 273:22848-55; PMID:9712920
43. Fabbro M, Zhou BB, Takahashi M, Sarcevic B, Lal P, Graham ME, Gabrielli BG, Robinson PJ, Nigg EA, Ono Y, et al. Cdk1/Erk2- and Plk1-dependent phosphorylation of a centrosome protein, Cep55, is required for its recruitment to midbody and cytokinesis. Dev Cell 2005; 9:477-88; PMID:16198290; http://dx.doi.org/10.1016/j.devcel.2005.09.003
44. Morton S, Davis RJ, McLaren A, Cohen P. A reinvestigation of the multisite phosphorylation of the transcription factor c-Jun. EMBO J 2003; 22:3876-86; PMID:12881422; http://dx.doi.org/10.1093/emboj/cdg388
45. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18:1926-45; PMID:15314020; http://dx.doi.org/10.1101/gad.1212704
46. Rigbolt KT, Zarei M, Sprenger A, Becker AC, Diedrich B, Huang X, Eiselein S, Kristensen AR, Gretzmeier C, Andersen JS, et al. Characterization of early autophagy signaling by quantitative phosphoproteomics. Autophagy 2013; 10; PMID:24275748.
47. Yu Y, Yoon SO, Poulogiannis G, Yang Q, Ma XM, Villén J, Kubica N, Hoffman GR, Cantley LC, Gygi SP, et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 2011; 332:1322-6; PMID:21659605; http://dx.doi.org/10.1126/science. 1199484
48. Lekmine F, Sassano A, Uddin S, Smith J, Majchrzak B, Brachmann SM, Hay N, Fish EN, Platanias LC. Interferon-gamma engages the p70 S6 kinase to regulate phosphorylation of the 40S S6 ribosomal protein. Exp Cell Res 2004; 295:173-82; PMID:15051500; http://dx.doi.org/10.1016/j.yexcr.2003.12.021
49. Matsuoka Y, Nagahara Y, Ikekita M, Shinomiya T. A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells. Br J Pharmacol 2003; 138:1303-12; PMID:12711631; http://dx.doi.org/10.1038/sj.bjp.0705182
50. Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 2007; 282:14056-64; PMID:17360704; http://dx.doi.org/10.1074/jbc.M700906200
51. Rigbolt KT, Prokhorova TA, Akimov V, Henningsen J, Johansen PT, Kratchmarova I, Kassem M, Mann M, Olsen JV, Blagoev B. System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation. Sci Signal 2011; 4:rs3; PMID:21406692; http://dx.doi.org/10.1126/scisignal.2001570
52. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, et al. Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal 2010; 3:ra3; PMID:20068231; http://dx.doi.org/10.1126/scisignal.2000475
53. Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 2003; 116:1175-86; PMID:12615961; http://dx.doi.org/10.1242/ jcs.00384
54. Fu L, Kim YA, Wang X, Wu X, Yue P, Lonial S, Khuri FR, Sun SY. Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy. Cancer Res 2009; 69:8967-76; PMID:19920197; http://dx.doi.org/10.1158/0008-5472.CAN-09- 2190
55. Mao JH, Kim IJ, Wu D, Climent J, Kang HC, DelRosario R, Balmain A. FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science 2008; 321:1499-502; PMID:18787170; http://dx.doi.org/10.1126/science. 1162981
56. Mariño G, Kroemer G. Ammonia: a diffusible factor released by proliferating cells that induces autophagy. Sci Signal 2010; 3:pe19; PMID:20516476; http://dx.doi.org/10.1126/scisignal.3124pe19
57. Schliess F, Görg B, Fischer R, Desjardins P, Bidmon HJ, Herrmann A, Butterworth RF, Zilles K, Häussinger D. Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. FASEB J 2002; 16:739-41; PMID:11923223
58. Jayakumar AR, Panickar KS, Murthy ChR, Norenberg MD. Oxidative stress and mitogen-activated protein kinase phosphorylation mediate ammonia-induced cell swelling and glutamate uptake inhibition in cultured astrocytes. J Neurosci 2006; 26:4774-84; PMID:16672650; http://dx.doi.org/10.1523/JNEUROSCI.0120-06. 2006
59. Vial E, Sahai E, Marshall CJ. ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility. Cancer Cell 2003; 4:67-79; PMID:12892714; http://dx.doi.org/10.1016/S1535-6108(03)00162-4
60. Torii S, Nakayama K, Yamamoto T, Nishida E. Regulatory mechanisms and function of ERK MAP kinases. J Biochem 2004; 136:557-61; PMID:15632293; http://dx.doi.org/10.1093/jb/mvh159
61. Shaul YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 2007; 1773:1213-26; PMID:17112607; http://dx.doi.org/10.1016/j.bbamcr.2006.10.005
62. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol 2002; 4:E131-6; PMID:11988758; http://dx.doi.org/10.1038/ncb0502-e131
63. Janknecht R, Ernst WH, Pingoud V, Nordheim A. Activation of ternary complex factor Elk-1 by MAP kinases. EMBO J 1993; 12:5097-104; PMID:8262053
64. Cassimeris L. The oncoprotein 18/stathmin family of microtubule destabilizers. Curr Opin Cell Biol 2002; 14:18-24; PMID:11792540; http://dx.doi.org/10.1016/S0955-0674(01)00289-7
65. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005; 121:179-93; PMID:15851026; http://dx.doi.org/10.1016/j.cell.2005.02.031
66. Pattingre S, Bauvy C, Codogno P. Amino acids interfere with the ERK1/2-dependent control of macroautophagy by controlling the activation of Raf-1 in human colon cancer HT-29 cells. J Biol Chem 2003; 278:16667-74; PMID:12609989; http://dx.doi.org/10.1074/jbc.M210998200
67. Webber JL, Tooze SA. Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP. EMBO J 2010; 29:27-40; PMID:19893488; http://dx.doi.org/10.1038/emboj.2009.321
68. Comes F, Matrone A, Lastella P, Nico B, Susca FC, Bagnulo R, Ingravallo G, Modica S, Lo Sasso G, Moschetta A, et al. A novel cell type-specific role of p38alpha in the control of autophagy and cell death in colorectal cancer cells. Cell Death Differ 2007; 14:693-702; PMID:17159917; http://dx.doi.org/10.1038/sj. cdd.4402076
69. Bustelo XR, Sauzeau V, Berenjeno IM. GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays 2007; 29:356-70; PMID:17373658; http://dx.doi.org/10.1002/bies.20558
70. Barnes WG, Reiter E, Violin JD, Ren XR, Milligan G, Lefkowitz RJ. beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation. J Biol Chem 2005; 280:8041-50; PMID:15611106; http://dx.doi.org/10.1074/jbc.M412924200
71. Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski S, et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 1999; 5:810-6; PMID:10395327; http://dx.doi.org/10.1038/10533
72. Kang JH, Jiang Y, Toita R, Oishi J, Kawamura K, Han A, Mori T, Niidome T, Ishida M, Tatematsu K, et al. Phosphorylation of Rho-associated kinase (Rhokinase/ROCK/ROK) substrates by protein kinases A and C. Biochimie 2007; 89:39-47; PMID:16996192; http://dx.doi.org/10.1016/j.biochi.2006.08.003
73. Reshkin SJ, Bellizzi A, Albarani V, Guerra L, Tommasino M, Paradiso A, Casavola V. Phosphoinositide 3-kinase is involved in the tumor-specific activation of human breast cancer cell Na(+)/H(+) exchange, motility, and invasion induced by serum deprivation. J Biol Chem 2000; 275:5361-9; PMID:10681510; http://dx.doi.org/10.1074/jbc.275.8.5361
74. Stock C, Gassner B, Hauck CR, Arnold H, Mally S, Eble JA, Dieterich P, Schwab A. Migration of human melanoma cells depends on extracellular pH and Na+/H+ exchange. J Physiol 2005; 567:225-38; PMID:15946960; http://dx.doi.org/ 10.1113/jphysiol.2005.088344
75. Kirkin V, McEwan DG, Novak I, Dikic I. A role for ubiquitin in selective autophagy. Mol Cell 2009; 34:259-69; PMID:19450525; http://dx.doi.org/10.1016/j. molcel.2009.04.026
76. Schneider M, Marison IW, von Stockar U. The importance of ammonia in mammalian cell culture. J Biotechnol 1996; 46:161-85; PMID:8672289; http://dx.doi.org/10.1016/0168-1656(95)00196-4
77. Warden SM, Richardson C, O'Donnell J Jr., Stapleton D, Kemp BE, Witters LA. Posttranslational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzyme activity and cellular localization. Biochem J 2001; 354:275-83; PMID:11171104; http://dx.doi.org/10.1042/0264-6021:3540275
78. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13:132-41; PMID:21258367; http://dx.doi.org/10.1038/ncb2152
79. Ito H, Iwamoto I, Inaguma Y, Takizawa T, Nagata K, Asano T, Kato K. Endoplasmic reticulum stress induces the phosphorylation of small heat shock protein, Hsp27. J Cell Biochem 2005; 95:932-41; PMID:15864808; http://dx.doi.org/10.1002/jcb.20445
80. Kanekura K, Nishimoto I, Aiso S, Matsuoka M. Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8). J Biol Chem 2006; 281:30223-33; PMID:16891305; http://dx.doi.org/10.1074/jbc.M605049200
81. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2000; 2:326-32; PMID:10854322; http://dx.doi.org/10.1038/35014014
82. Devi L, Alldred MJ, Ginsberg SD, Ohno M. Mechanisms underlying insulin deficiency-induced acceleration of β-amyloidosis in a mouse model of Alzheimer's disease. PLoS One 2012; 7:e32792; PMID:22403710; http://dx.doi.org/10.1371/journal.pone.0032792
83. Gjymishka A, Su N, Kilberg MS. Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway. Biochem J 2009; 417:695-703; PMID:18840095; http://dx.doi.org/10.1042/BJ20081706
84. Tian T, Zhao Y, Nakajima S, Huang T, Yao J, Paton AW, Paton JC, Kitamura M. Cytoprotective roles of ERK and Akt in endoplasmic reticulum stress triggered by subtilase cytotoxin. Biochem Biophys Res Commun 2011; 410:852-8; PMID:21703246; http://dx.doi.org/10.1016/j.bbrc.2011.06.078
85. Hu P, Han Z, Couvillon AD, Exton JH. Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death. J Biol Chem 2004; 279:49420-9; PMID:15339911; http://dx.doi.org/10. 1074/jbc.M407700200
86. Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, Kaufman RJ, Kominami E, Momoi T. ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 2007; 14:230-9; PMID:16794605; http://dx.doi.org/10.1038/sj.cdd.4401984
87. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 2006; 26:9220-31; PMID:17030611; http://dx.doi.org/10.1128/MCB.01453-06
88. Ong SE, Blagoev B, Kratchmarova I, Kristensen DB, Steen H, Pandey A, Mann M. Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol Cell Proteomics 2002; 1:376-86; PMID:12118079; http://dx.doi.org/10.1074/mcp.M200025-MCP200
89. Rappsilber J, Ishihama Y, Mann M. Stop and go extraction tips for matrix-assisted laser desorption/ ionization, nanoelectrospray, and LC/MS sample pretreatment in proteomics. Anal Chem 2003; 75:663-70; PMID:12585499; http://dx.doi.org/10.1021/ac026117i
90. Larsen MR, Thingholm TE, Jensen ON, Roepstorff P, Jørgensen TJ. Highly selective enrichment of phosphorylated peptides from peptide mixtures using titanium dioxide microcolumns. Mol Cell Proteomics 2005; 4:873-86; PMID:15858219; http://dx.doi.org/10.1074/mcp.T500007-MCP200
91. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 2008; 26:1367-72; PMID:19029910; http://dx.doi.org/10.1038/nbt.1511