MAPK/ERK Signaling Regulates Insulin Sensitivity to Control Glucose Metabolism in

English version České info

The insulin/IGF-activated AKT signaling pathway plays a crucial role in regulating tissue growth and metabolism in multicellular animals. Although core components of the pathway are well defined, less is known about mechanisms that adjust the sensitivity of the pathway to extracellular stimuli. In humans, disturbance in insulin sensitivity leads to impaired clearance of glucose from the blood stream, which is a hallmark of diabetes. Here we present the results of a genetic screen in Drosophila designed to identify regulators of insulin sensitivity in vivo. Components of the MAPK/ERK pathway were identified as modifiers of cellular insulin responsiveness. Insulin resistance was due to downregulation of insulin-like receptor gene expression following persistent MAPK/ERK inhibition. The MAPK/ERK pathway acts via the ETS-1 transcription factor Pointed. This mechanism permits physiological adjustment of insulin sensitivity and subsequent maintenance of circulating glucose at appropriate levels.

Vyšlo v časopise: MAPK/ERK Signaling Regulates Insulin Sensitivity to Control Glucose Metabolism in. PLoS Genet 7(12): e32767. doi:10.1371/journal.pgen.1002429
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002429

Souhrn

Zdroje

1. ManningBDCantleyLC 2007 AKT/PKB signaling: navigating downstream. Cell 129 1261 1274

2. HietakangasVCohenSM 2009 Regulation of tissue growth through nutrient sensing. Annu Rev Genet 43 389 410

3. EngelmanJALuoJCantleyLC 2006 The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7 606 619

4. SarbassovDDGuertinDAAliSMSabatiniDM 2005 Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307 1098 1101

5. HreskoRCMuecklerM 2005 mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 280 40406 40416

6. HietakangasVCohenSM 2007 Re-evaluating AKT regulation: role of TOR complex 2 in tissue growth. Genes Dev 21 632 637

7. HuangHTindallDJ 2007 Dynamic FoxO transcription factors. J Cell Sci 120 2479 2487

8. InokiKLiYZhuTWuJGuanKL 2002 TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4 648 657

9. PotterCJPedrazaLGXuT 2002 Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 4 658 665

10. SancakYThoreenCCPetersonTRLindquistRAKangSA 2007 PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25 903 915

11. Vander HaarELeeSIBandhakaviSGriffinTJKimDH 2007 Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9 316 323

12. HarringtonLSFindlayGMGrayATolkachevaTWigfieldS 2004 The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166 213 223

13. ShahOJWangZHunterT 2004 Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 14 1650 1656

14. YangRTrevillyanJM 2008 c-Jun N-terminal kinase pathways in diabetes. Int J Biochem Cell Biol 40 2702 2706

15. JungerMARintelenFStockerHWassermanJDVeghM 2003 The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J Biol 2 20

16. ShaulYDSegerR 2007 The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 1773 1213 1226

17. O'NeillEMRebayITjianRRubinGM 1994 The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway. Cell 78 137 147

18. GenevetAWehrMCBrainRThompsonBJTaponN 2010 Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev Cell 18 300 308

19. RoyFLabergeGDouziechMFerland-McColloughDTherrienM 2002 KSR is a scaffold required for activation of the ERK/MAPK module. Genes Dev 16 427 438

20. AnselmoANBumeisterRThomasJMWhiteMA 2002 Critical contribution of linker proteins to Raf kinase activation. J Biol Chem 277 5940 5943

21. BrittonJSLockwoodWKLiLCohenSMEdgarBA 2002 Drosophila's Insulin/PI3-Kinase Pathway Coordinates Cellular Metabolism with Nutritional Conditions. Dev Cell 2 239 249

22. WullschlegerSLoewithRHallMN 2006 TOR signaling in growth and metabolism. Cell 124 471 484

23. GaoXZhangYArrazolaPHinoOKobayashiT 2002 Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 4 699 704

24. O'NeillEMRebayITjianRRubinGM 1994 The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway. Cell 78 137 147

25. BrunnerDDuckerKOellersNHafenEScholzH 1994 The ETS domain protein pointed-P2 is a target of MAP kinase in the sevenless signal transduction pathway. Nature 370 386 389

26. RogersEMBrennanCAMortimerNTCookSMorrisAR 2005 Pointed regulates an eye-specific transcriptional enhancer in the Drosophila hedgehog gene, which is required for the movement of the morphogenetic furrow. Development 132 4833 4843

27. TelemanAA 2010 Molecular mechanisms of metabolic regulation by insulin in Drosophila. Biochem J 425 13 26

28. BeckerASchloderPSteeleJEWegenerG 1996 The regulation of trehalose metabolism in insects. Experientia 52 433 439

29. BroughtonSJPiperMDIkeyaTBassTMJacobsonJ 2005 Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc Natl Acad Sci U S A 102 3105 3110

30. WelshGIHersIBerwickDCDellGWherlockM 2005 Role of protein kinase B in insulin-regulated glucose uptake. Biochem Soc Trans 33 346 349

31. EckelRHAlbertiKGGrundySMZimmetPZ 2010 The metabolic syndrome. Lancet 375 181 183

32. Rodriguez-VicianaPWarnePHDhandRVanhaesebroeckBGoutI 1994 Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370 527 532

33. OrmeMHAlrubaieSBradleyGLWalkerCDLeeversSJ 2006 Input from Ras is required for maximal PI(3)K signalling in Drosophila. Nat Cell Biol 8 1298 1302

34. AlonU 2007 Network motifs: theory and experimental approaches. Nat Rev Genet 8 450 461

35. LiXCassidyJJReinkeCAFischboeckSCarthewRW 2009 A microRNA imparts robustness against environmental fluctuation during development. Cell 137 273 282

36. PuigOMarrMTRuhfMLTjianR 2003 Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev 17 2006 2020

37. PuigOTjianR 2005 Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev 19 2435 2446

38. StewartMJBerryCOZilbermanFThomasGKozmaSC 1996 The Drosophila p70s6k homolog exhibits conserved regulatory elements and rapamycin sensitivity. Proc Natl Acad Sci U S A 93 10791 10796