Apoptosis

, Volume 14, Issue 5, pp 665–673

Insulin receptor substrate (IRS)-2, not IRS-1, protects human neuroblastoma cells against apoptosis

Original Paper

Abstract

Insulin receptor substrates (IRS)-1 and -2 are major substrates of insulin and type I insulin-like growth factor (IGF-I) receptor (IGF-IR) signaling. In this study, SH-EP human neuroblastoma cells are used as a model system to examine the differential roles of IRS-1 and IRS-2 on glucose-mediated apoptosis. In the presence of high glucose, IRS-1 underwent caspase-mediated degradation, followed by focal adhesion kinase (FAK) and Akt degradation and apoptosis. IRS-2 expression blocked all these changes whereas IRS-1 overexpression had no effect. In parallel, IRS-2, but not IRS-1, overexpression enhanced IGF-I-mediated Akt activation without affecting extracellular regulated kinase signaling. While IRS-1 was readily degraded by caspases, hyperglycemia-mediated IRS-2 degradation was unaffected by caspase inhibitors but blocked by proteasome and calpain inhibitors. Our data suggest that the differential degradation of IRS-1 and IRS-2 contributes to their distinct modes of action and the increased neuroprotective effects of IRS-2 in this report are due, in part, to its resistance to caspase-mediated degradation.

Keywords

IRS Apoptosis Caspase Neuroblastoma 

References

  1. 1.
    Laviola L, Natalicchio A, Giorgino F (2007) The IGF-I signaling pathway. Curr Pharm Des 13:663–669. doi:10.2174/138161207780249146 CrossRefPubMedGoogle Scholar
  2. 2.
    Zumkeller W, Schwab M (1999) Insulin-like growth factor system in neuroblastoma tumorigenesis and apoptosis: potential diagnostic and therapeutic perspectives. Horm Metab Res 31:138–141. doi:10.1055/s-2007-978711 CrossRefPubMedGoogle Scholar
  3. 3.
    Riedemann J, Macaulay VM (2006) IGF1R signalling and its inhibition. Endocr Relat Cancer 13(Suppl 1):S33–S43. doi:10.1677/erc.1.01280 CrossRefPubMedGoogle Scholar
  4. 4.
    Lee YH, White MF (2004) Insulin receptor substrate proteins and diabetes. Arch Pharm Res 27:361–370. doi:10.1007/BF02980074 CrossRefPubMedGoogle Scholar
  5. 5.
    Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF (1999) Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet 23:32–40PubMedGoogle Scholar
  6. 6.
    Withers DJ, Gutierrez JS, Towery H et al (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904. doi:10.1038/36116 CrossRefPubMedGoogle Scholar
  7. 7.
    Schubert M, Brazil DP, Burks DJ et al (2003) Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci 23:7084–7092PubMedGoogle Scholar
  8. 8.
    Boissan M, Beurel E, Wendum D et al (2005) Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. Am J Pathol 167:869–877PubMedGoogle Scholar
  9. 9.
    Rother KI, Imai Y, Caruso M, Beguinot F, Formisano P, Accili D (1998) Evidence that IRS-2 phosphorylation is required for insulin action in hepatocytes. J Biol Chem 273:17491–17497. doi:10.1074/jbc.273.28.17491 CrossRefPubMedGoogle Scholar
  10. 10.
    Tseng YH, Ueki K, Kriauciunas KM, Kahn CR (2002) Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. J Biol Chem 277:31601–31611. doi:10.1074/jbc.M202932200 CrossRefPubMedGoogle Scholar
  11. 11.
    Li L, Qi X, Williams M, Shi Y, Keegan AD (2002) Overexpression of insulin receptor substrate-1, but not insulin receptor substrate-2, protects a T cell hybridoma from activation-induced cell death. J Immunol 168:6215–6223PubMedGoogle Scholar
  12. 12.
    Leinninger GM, Russell JW, van Golen CM, Berent A, Feldman EL (2004) Insulin-like growth factor-I regulates glucose-induced mitochondrial depolarization and apoptosis in human neuroblastoma. Cell Death Differ 11:885–896. doi:10.1038/sj.cdd.4401429 CrossRefPubMedGoogle Scholar
  13. 13.
    Van Golen CM, Feldman EL (2000) Insulin-like growth factor I is the key growth factor in serum that protects neuroblastoma cells from hyperosmotic-induced apoptosis. J Cell Physiol 182:24–32. doi:10.1002/(SICI)1097-4652(200001)182:1<24::AID-JCP3>3.0.CO;2-6 CrossRefPubMedGoogle Scholar
  14. 14.
    Russell JW, Feldman EL (1999) Insulin-like growth factor-I prevents apoptosis in sympathetic neurons exposed to high glucose. Horm Metab Res 31:90–96. doi:10.1055/s-2007-978704 CrossRefPubMedGoogle Scholar
  15. 15.
    van Golen CM, Castle VP, Feldman EL (2000) IGF-I receptor activation and BCL-2 overexpression prevent early apoptotic events in human neuroblastoma. Cell Death Differ 7:654–665. doi:10.1038/sj.cdd.4400693 CrossRefPubMedGoogle Scholar
  16. 16.
    Kim B, Feldman EL (2002) Insulin-like growth factor I prevents mannitol-induced degradation of focal adhesion kinase and Akt. J Biol Chem 277:27393–27400. doi:10.1074/jbc.M201963200 CrossRefPubMedGoogle Scholar
  17. 17.
    Kim B, van Golen CM, Feldman EL (2005) Insulin-like growth factor I induces preferential degradation of insulin receptor substrate-2 through the phosphatidylinositol 3-kinase pathway in human neuroblastoma cells. Endocrinology 146:5350–5357. doi:10.1210/en.2005-0356 CrossRefPubMedGoogle Scholar
  18. 18.
    Devary Y, Gottlieb RA, Smeal T, Karin M (1992) The mammalian ultraviolet response is triggered by activation of Src tyrosine kinases. Cell 71:1081–1091. doi:10.1016/S0092-8674(05)80058-3 CrossRefPubMedGoogle Scholar
  19. 19.
    Castleberry RP (1997) Biology and treatment of neuroblastoma. Pediatr Clin North Am 44:919–937. doi:10.1016/S0031-3955(05)70537-X CrossRefPubMedGoogle Scholar
  20. 20.
    Schmidt ML, Lukens JN, Seeger RC et al (2000) Biologic factors determine prognosis in infants with stage IV neuroblastoma: a prospective Children’s Cancer Group study. J Clin Oncol 18:1260–1268PubMedGoogle Scholar
  21. 21.
    Kim PK, Mahidhara R, Seol DW (2001) The role of caspase-8 in resistance to cancer chemotherapy. Drug Resist Updat 4:293–296. doi:10.1054/drup.2001.0223 CrossRefPubMedGoogle Scholar
  22. 22.
    Lee AV, Gooch JL, Oesterreich S, Guler RL, Yee D (2000) Insulin-like growth factor I-induced degradation of insulin receptor substrate 1 is mediated by the 26S proteasome and blocked by phosphatidylinositol 3′-kinase inhibition. Mol Cell Biol 20:1489–1496. doi:10.1128/MCB.20.5.1489-1496.2000 CrossRefPubMedGoogle Scholar
  23. 23.
    Kim B, Leventhal PS, Saltiel AR, Feldman EL (1997) Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires mitogen-activated protein kinase activation. J Biol Chem 272:21268–21273. doi:10.1074/jbc.272.34.21268 CrossRefPubMedGoogle Scholar
  24. 24.
    Kim B, van Golen CM, Feldman EL (2004) Insulin-like growth factor-I signaling in human neuroblastoma cells. Oncogene 23:130–141. doi:10.1038/sj.onc.1206924 CrossRefPubMedGoogle Scholar
  25. 25.
    Kim B, Oh S, van Golen CM, Feldman EL (2005) Differential regulation of insulin receptor substrate-1 degradation during mannitol and okadaic acid induced apoptosis in human neuroblastoma cells. Cell Signal 17:769–775. doi:10.1016/j.cellsig.2004.11.001 CrossRefPubMedGoogle Scholar
  26. 26.
    Cheng HL, Steinway M, Delaney CL, Franke TF, Feldman EL (2000) IGF-I promotes Schwann cell motility and survival via activation of Akt. Mol Cell Endocrinol 170:211–215. doi:10.1016/S0303-7207(00)00324-5 CrossRefPubMedGoogle Scholar
  27. 27.
    Vincent AM, Mobley BC, Hiller A, Feldman EL (2004) IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiol Dis 16:407–416. doi:10.1016/j.nbd.2004.03.001 CrossRefPubMedGoogle Scholar
  28. 28.
    Chang HY, Yang X (2000) Proteases for cell suicide: functions and regulation of caspases. Microbiol Mol Biol Rev 64:821–846. doi:10.1128/MMBR.64.4.821-846.2000 CrossRefPubMedGoogle Scholar
  29. 29.
    Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, Kasahara T (2000) Anti-apoptotic role of focal adhesion kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. J Biol Chem 275:16309–16315. doi:10.1074/jbc.275.21.16309 CrossRefPubMedGoogle Scholar
  30. 30.
    Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE (2004) Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells. Surgery 135:555–562. doi:10.1016/j.surg.2003.10.017 CrossRefPubMedGoogle Scholar
  31. 31.
    Frebel K, Wiese S (2006) Signalling molecules essential for neuronal survival and differentiation. Biochem Soc Trans 34:1287–1290. doi:10.1042/BST0341287 CrossRefPubMedGoogle Scholar
  32. 32.
    Kim B, Cheng HL, Margolis B, Feldman EL (1998) Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling. J Biol Chem 273:34543–34550. doi:10.1074/jbc.273.51.34543 CrossRefPubMedGoogle Scholar
  33. 33.
    Valverde AM, Fabregat I, Burks DJ, White MF, Benito M (2004) IRS-2 mediates the antiapoptotic effect of insulin in neonatal hepatocytes. Hepatology 40:1285–1294. doi:10.1002/hep.20485 CrossRefPubMedGoogle Scholar
  34. 34.
    Lingohr MK, Dickson LM, Wrede CE et al (2003) Decreasing IRS-2 expression in pancreatic beta-cells (INS-1) promotes apoptosis, which can be compensated for by introduction of IRS-4 expression. Mol Cell Endocrinol 209:17–31. doi:10.1016/j.mce.2003.08.003 CrossRefPubMedGoogle Scholar
  35. 35.
    Cosaceanu D, Carapancea M, Alexandru O et al (2007) Comparison of three approaches for inhibiting insulin-like growth factor I receptor and their effects on NSCLC cell lines in vitro. Growth Factors 25:1–8. doi:10.1080/08977190600702865 CrossRefPubMedGoogle Scholar
  36. 36.
    Edderkaoui M, Hong P, Lee JK, Pandol SJ, Gukovskaya AS (2007) Insulin-like growth factor-I receptor mediates the prosurvival effect of fibronectin. J Biol Chem 282:26646–26655. doi:10.1074/jbc.M702836200 CrossRefPubMedGoogle Scholar
  37. 37.
    Neid M, Datta K, Stephan S et al (2004) Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells. J Biol Chem 279:3941–3948. doi:10.1074/jbc.M303975200 CrossRefPubMedGoogle Scholar
  38. 38.
    Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM (2004) Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol Cell Biol 24:9726–9735. doi:10.1128/MCB.24.22.9726-9735.2004 CrossRefPubMedGoogle Scholar
  39. 39.
    Hanks SK, Ryzhova L, Shin NY, Brabek J (2003) Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility. Front Biosci 8:d982–d996. doi:10.2741/1114 CrossRefPubMedGoogle Scholar
  40. 40.
    Toker A, Yoeli-Lerner M (2006) Akt signaling and cancer: surviving but not moving on. Cancer Res 66:3963–3966. doi:10.1158/0008-5472.CAN-06-0743 CrossRefPubMedGoogle Scholar
  41. 41.
    Kim B, van Golen CM, Feldman EL (2003) Degradation and dephosphorylation of focal adhesion kinase during okadaic acid-induced apoptosis in human neuroblastoma cells. Neoplasia 5:405–416PubMedGoogle Scholar
  42. 42.
    Demarchi F, Schneider C (2007) The calpain system as a modulator of stress/damage response. Cell Cycle 6:136–138PubMedGoogle Scholar
  43. 43.
    Zhang H, Hoff H, Sell C (2003) Downregulation of IRS-1 protein in thapsigargin-treated human prostate epithelial cells. Exp Cell Res 289:352–358. doi:10.1016/S0014-4827(03)00286-6 CrossRefPubMedGoogle Scholar
  44. 44.
    Briaud I, Dickson LM, Lingohr MK, McCuaig JF, Lawrence JC, Rhodes CJ (2005) Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in beta-cells. J Biol Chem 280:2282–2293. doi:10.1074/jbc.M412179200 CrossRefPubMedGoogle Scholar
  45. 45.
    Ando K, Fujita T (2004) Role of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in the development of hypertensive organ damage. Clin Exp Nephrol 8:178–182. doi:10.1007/s10157-004-0288-9 CrossRefPubMedGoogle Scholar
  46. 46.
    Simmons JG, Ling Y, Wilkins H et al (2007) Cell-specific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth. Am J Physiol Gastrointest Liver Physiol 293:G995–G1003. doi:10.1152/ajpgi.00537.2006 CrossRefPubMedGoogle Scholar
  47. 47.
    Lebrun P, Mothe-Satney I, Delahaye L, Van Obberghen E, Baron V (1998) Insulin receptor substrate-1 as a signaling molecule for focal adhesion kinase pp125(FAK) and pp60(src). J Biol Chem 273:32244–32253. doi:10.1074/jbc.273.48.32244 CrossRefPubMedGoogle Scholar
  48. 48.
    Bouchard V, Demers MJ, Thibodeau S et al (2007) Fak/Src signaling in human intestinal epithelial cell survival and anoikis: differentiation state-specific uncoupling with the PI3-K/Akt-1 and MEK/Erk pathways. J Cell Physiol 212:717–728. doi:10.1002/jcp.21096 CrossRefPubMedGoogle Scholar
  49. 49.
    Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9:59–71. doi:10.1111/j.1582-4934.2005.tb00337.x CrossRefPubMedGoogle Scholar
  50. 50.
    Blanco-Aparicio C, Renner O, Leal JF, Carnero A (2007) PTEN, more than the AKT pathway. Carcinogenesis 28:1379–1386. doi:10.1093/carcin/bgm052 CrossRefPubMedGoogle Scholar
  51. 51.
    van Golen CM, Schwab TS, Ignatoski KM, Ethier SP, Feldman EL (2001) PTEN/MMAC1 overexpression decreases insulin-like growth factor-I-mediated protection from apoptosis in neuroblastoma cells. Cell Growth Differ 12:371–378PubMedGoogle Scholar
  52. 52.
    Mian MF, Kang C, Lee S et al (2008) Cleavage of focal adhesion kinase is an early marker and modulator of oxidative stress-induced apoptosis. Chem Biol Interact 171:57–66. doi:10.1016/j.cbi.2007.08.009 CrossRefPubMedGoogle Scholar
  53. 53.
    Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S (1998) Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 95:11211–11216. doi:10.1073/pnas.95.19.11211 CrossRefPubMedGoogle Scholar
  54. 54.
    Franke TF, Kaplan DR, Cantley LC (1997) PI3 K: downstream AKTion blocks apoptosis. Cell 88:435–437. doi:10.1016/S0092-8674(00)81883-8 CrossRefPubMedGoogle Scholar
  55. 55.
    Kim B, Leventhal PS, White MF, Feldman EL (1998) Differential regulation of insulin receptor substrate-2 and mitogen-activated protein kinase tyrosine phosphorylation by phosphatidylinositol 3-kinase inhibitors in SH-SY5Y human neuroblastoma cells. Endocrinology 139:4881–4889. doi:10.1210/en.139.12.4881 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of MichiganAnn ArborUSA

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