Functions as a Positive Regulator of Growth and Metabolism in

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Size and growth of an organism are adjusted to nutritional conditions by a complex regulatory network involving the Insulin receptor and TOR signaling cascades. Drosophila melanogaster has been used in the past as a genetically tractable model to unravel the complex circuitry by genetic means. We have identified CycG as an important player in the regulation of TOR signaling. CycG mutants are underweight in the midst of food and show typical signs of TOR defects. We provide evidence that CycG acts at the level of Akt1 kinase that links the Insulin receptor and TOR signaling cascades. Molecular and genetic data point to an interplay of CycG and phosphatase PP2A, a well established negative regulator of Akt1 activity. Moreover, CycG may influence PP2A-Akt1 binding. We propose that CycG, by impeding PP2A-Akt1 interaction, acts as a positive regulator of growth in Drosophila.

Vyšlo v časopise: Functions as a Positive Regulator of Growth and Metabolism in. PLoS Genet 11(8): e32767. doi:10.1371/journal.pgen.1005440
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005440

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Zdroje

1. Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol. 2005; 17: 156–166.

2. Teleman AA. Molecular mechanisms of metabolic regulation by insulin in Drosophila. Biochem J. 2010; 425: 13–26.

3. Brogiolo W, Stocker H, Ikeya T, Rintelen F, Fernandez R, Hafen E. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol. 2001; 11: 213–221. 11250149

4. Géminard C, Rulifson EJ, Léopold P. Remote control of Insulin secretion by fat cells in Drosophila. Cell Metab. 2009; 10: 199–207. doi: 10.1016/j.cmet.2009.08.002 19723496

5. Rulifson EJ, Kim SK, Nusse R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 2002; 296: 1118–1120. 12004130

6. Colombani J, Andersen DS, Léopold P. Secreted peptide Dilp8 coordinates Drosophila tissue growth with developmental timing. Science 2012; 336: 582–585. doi: 10.1126/science.1216689 22556251

7. Garelli A, Gontijo AM, Miguela V, Caparros E, Dominguez M. Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation. Science 2012; 336: 579–582. doi: 10.1126/science.1216735 22556250

8. Fayard E, Tintignac LA, Baudry A, Hemmings BA. Protein kinase B/Akt at a glance. J. Cell Sci. 2005; 118: 5675–5678. 16339964

9. Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol. 2002; 4: 699–704. 12172555

10. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003; 11: 1457–1466. 12820960

11. Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003; 17: 1829–1834. 12869586

12. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol. 2003; 5: 566–571. 12766776

13. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol. 2003; 5: 578–581. 12771962

14. Goberdhan DC, Paricio N, Goodman EC, Mlodzik M, Wilson C. Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev. 1999; 13: 3244–3258. 10617573

15. Hahn K, Miranda M, Francis VA, Vendrell J, Zorzano A, Teleman AA. PP2A regulatory subunit PP2A-B' counteracts S6K phosphorylation. Cell Metab. 2010; 11: 438–444. doi: 10.1016/j.cmet.2010.03.015 20444422

16. Funakoshi M, Tsuda M, Muramatsu K, Hatsuda H, Morishita S, Aigaki T. A gain of function screen identifies wdb and lkb1 as lifespan-extending genes in Drosophila. Biochem Biophys Res Commun. 2011; 405:667–672. doi: 10.1016/j.bbrc.2011.01.090 21281604

17. Padmanabhan S, Mukhopadhyay A, Narasimhan SD, Tesz G, Czech MP, Tissenbaum HA. A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell 2009; 136: 939–951. doi: 10.1016/j.cell.2009.01.025 19249087

18. Vereshchagina N, Ramel MC, Bitoun E, Wilson C. The protein phosphatase PP2A-B' subunit Widerborst is a negative regulator of cytoplasmic activated Akt and lipid metabolism in Drosophila. J Cell Sci. 2008; 121: 3383–3392. doi: 10.1242/jcs.035220 18827008

19. Oldham S, Montagne J, Radimerski T, Thomas G, Hafen E. Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev. 2000; 14: 2689–2694. 11069885

20. Zhang H, Stallock JP, Ng JC, Reinhard C, Neufeld TP. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 2000; 14: 2712–2724. 11069888

21. Rajan A, Perrimon N. Drosophila as a model for interorgan communication: lessons from studies on energy homeostasis. Dev Cell 2011; 21:29–31 doi: 10.1016/j.devcel.2011.06.034 21763605

22. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 24: 471–484.

23. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004; 18: 1926–1945. 15314020

24. Nagel AC, Fischer P, Szawinski J, La Rosa MK, Preiss A. Cyclin G is involved in meiotic recombination repair in Drosophila melanogaster. J Cell Sci. 2012; 125: 5555–5563. doi: 10.1242/jcs.113902 22976300

25. Nagel AC, Szawinski J, Fischer P, Maier D, Wech I, Preiss A. Dorso-ventral axis formation of the Drosophila oocyte requires Cyclin G. Hereditas 2012; 149: 186–196. doi: 10.1111/j.1601-5223.2012.02273.x 23121330

26. Faradji F, Bloyer S, Dardalhon-Cuménal D, Randsholt NB, Peronnet F. Drosophila melanogaster Cyclin G coordinates cell growth and proliferation. Cell Cycle 2011; 10: 805–818. 21311225

27. Giot L, Bader JS, Brouwer C, Chaudhuri A, Kuang B, Li Y, et al. A protein interaction map of Drosophila melanogaster. Science 2003; 302: 1727–1736. 14605208

28. Stanyon CA, Liu G, Mangiola BA, Patel N, Giot L, Kuang B, et al. A Drosophila protein-interaction map centered on cell-cycle regulators. Genome Biol. 2004; 5(12): R96. 15575970

29. Böhni R, Riesgo-Escovar J, Oldham S, Brogiolo W, Stocker H, Andruss AF, et al. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 1999; 97: 865–875. 10399915

30. Xu T, Rubin GM. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 1993; 117: 1223–1237. 8404527

31. Gong WJ, Golic KG. Ends-out, or replacement, gene targeting in Drosophila. Proc Natl Acad Sci. USA 2003; 100: 2556–2561. 12589026

32. Reis T, Van Gilst MR, Hariharan IK. A buoyancy-based screen of Drosophila larvae for fat storage mutants reveals a role for Sir2 in coupling fat storage to nutrient availability. PLOS Genet. 2010; 6(11): e1001206. doi: 10.1371/journal.pgen.1001206 21085633

33. Gutierrez E, Wiggins D, Fielding B, Gould AP. Specialized hepatocyte-like cells regulate Drosophila lipid metabolism. Nature 2007; 445: 275–280. 17136098

34. Grönke S, Mildner A, Fellert S, Tennagels N, Petry S, Müller G, et al. Brummer lipase is an evolutionary conserved fat storage regulator in Drosophila. Cell Metab. 2005; 1: 323–330. 16054079

35. Colombani J, Raisin S, Pantalacci S, Radimerski T, Montagne J, Léopold P. A nutrient sensor mechanism controls Drosophila growth. Cell 2003; 114: 739–749. 14505573

36. Ikeya T, Galic M, Belawat P, Nairz K, Hafen E. Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila. Curr Biol. 2002; 12: 1293–1300. 12176357

37. Park S, Alfa RW, Topper SM, Kim GES, Kockel L, Kim SK. A genetic strategy to measure circulating Drosophila insulin reveals genes regulating insulin production and secretion. PLOS Genet. 2014; 10: e1004555. doi: 10.1371/journal.pgen.1004555 25101872

38. LaFever L, Drummond-Barbosa D. Direct control of germline stem cell division and cyst growth by neural insulin in Drosophila. Science 2005; 309: 1071–1073. 16099985

39. Britton JS, Lockwood WK, Li L, Cohen SM, Edgar BA. Drosophila's Insulin/PI3-Kinase pathway coordinates cellular metabolism with nutritional conditions. Dev Cell 2002; 2: 239–249. 11832249

40. Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J. 2001; 353: 417–439. 11171037

41. Bennin DA, Arachchige Don AS, Brake T, McKenzie JL, Rosenbaum H, Ortiz L, et al. Cyclin G2 associates with Protein Phosphatase 2A catalytic and regulatory B’ subunits in active complexes and induces nuclear aberrations and a G1/S phase cell cycle arrest. J Biol Chem. 2002; 277: 27449–27467. 11956189

42. Okamoto K, Li H, Jensen MR, Zhang T, Taya Y, Thorgeirsson SS, et al. Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell 2002; 9: 761–771. 11983168

43. Hannus M, Feiguin F, Heisenberg CP, Eaton S. Planar cell polarization requires Widerborst, a B' regulatory subunit of protein phosphatase 2A. Development 2002; 129: 3494–3503.

44. Wilson C, Vereshchagina N, Reynolds B, Meredith D, Boyd CAR, Goberdhan DCI. Extracellular and subcellular regulation of the PI3K/Akt cassette: new mechanisms for controlling insulin and growth factor signalling. Biochem Soc Trans. 2007; 35: 219–221. 17371242

45. Vereshchagina N, Wilson C. Cytoplasmic activated protein kinase Akt regulates lipid-droplet accumulation in Drosophila nurse cells. Development 2006; 133: 4731–4735. 17079271

46. Salvaing J, Nagel AC, Mouchel-Vielh E, Bloyer S, Maier D, Preiss A, et al. The Enhancer of Trithorax and Polycomb Corto interacts with Cyclin G in Drosophila. PLOS One 2008; 3(2):e1658. doi: 10.1371/journal.pone.0001658 18286205

47. Debat V, Bloyer S, Faradji F, Gidaszewski N, Navarro N, Orozco-Terwengel P, et al. Developmental stability: a major role for cyclin G in Drosophila melanogaster. PLOS Genet. 2011; 7: e1002314. doi: 10.1371/journal.pgen.1002314 21998598

48. Kurimchak A, Graña X. PP2A counterbalances phosphorylation of pRB and mitotic proteins by multiple CDKs: Potential implications for PP2A disruption in cancer. Genes Cancer 2012; 3: 739–748. doi: 10.1177/1947601912473479 23634261

49. Chowdhury D, Keogh MC, Ishii H, Peterson CL, Buratowski S, Lieberman J. Gamma-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair. Mol Cell 2005; 20: 801–809. 16310392

50. Kimura SH, Ikawa M, Ito A, Okabe M, Nojima H. Cyclin G1 is involved in G2/M arrest response to DNA damage and in growth control after damage recovery. Oncogene 2001; 20: 3290–3300. 11423978

51. Zimmermann M, Arachchige-Don AS, Donaldson MS, Dappapiazza RF, Cowen CE, Horne MC. Elevated cyclin G2 expression intersects with DNA damage checkpoint signaling and is required for a potent G2/M checkpoint arrest response to doxorubicin. J Biol Chem 2012; 287: 22838–22853. doi: 10.1074/jbc.M112.376855 22589537

52. Kockel L, Kerr KS, Melnick M, Brückner K, Hebrock M, Perrimon N. Dynamic switch of negative feedback regulation in Drosophila Akt-TOR signaling. PLOS Genet. 2010; 6:e1000990. doi: 10.1371/journal.pgen.1000990 20585550

53. Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans. 2009; 37: 217–222. doi: 10.1042/BST0370217 19143635

54. Maier D, Marquart J, Thompson-Fontaine A, Beck I, Wurmbach E, Preiss A. In vivo structure-function analysis of Drosophila Hairless. Mech Dev. 1997; 67: 97–106. 9347918

55. Rubin GM, Spradling AC. Genetic transformation of Drosophila with transposable element vectors. Science 1982; 218: 348–353. 6289436

56. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK. The Drosophila Tuberous Sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 2001; 105: 345–355. 11348591

57. Tautz D, Pfeifle C. A non-radioactive in situ hybridization method for the localization of specific RNAs in Drosophila embryos reveals translational control of the segmentation gene hunchback. Chromosoma 1989; 98: 81–85. 2476281

58. Miron M, Verdú J, Lachance PE, Birnbaum MJ, Lasko PF, Sonenberg N. The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth in Drosophila. Nat Cell Biol. 2001; 3: 596–601. 11389445

59. Gyuris J, Golemis E, Chertkov H, Brent R. Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2. Cell 1993; 75: 791–803. 8242750

60. Hollenberg SM, Sternglanz R, Cheng PF, Weintraub H. Identification of a new family of tissue-specific basic helix-loop-helix proteins with a two-hybrid system. Mol Cell Biol 1995; 15: 3813–3822. 7791788