Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Insulin-like growth factor-I signaling in human neuroblastoma cells

Oncogene volume 23, pages 130–141 (2004)Cite this article

Abstract

Neuroblastoma is a heterogeneous tumor consisting of N (neuronal) and S (stromal) cells. We report that more tumorigenic and motile N cells express higher levels of IGF-I receptor (IGF-IR) than less tumorigenic, more adherent S cells. Shc, one of the two major docking partners of IGF-IR, is equally expressed in N and S cell lines. IGF-I treatment phosphorylates Shc in N cells, but only weakly activates Shc in S cells. Expression of the second partner, insulin receptor substrate (IRS), is cell type specific. S cells exclusively express IRS-1 that undergoes sustained phosphorylation by IGF-I. In contrast, N cells express IRS-2 that is transiently phosphorylated by IGF-I. Downstream of IRS-2 and Shc, IGF-I treatment results in strong activation of Akt and MAPK in N cells and activation of both pathways is required for IGF-I-mediated differentiation. Only IGF-IR activation of phosphatidylinositol-3 kinase is required for tumor edge ruffling in N and S cells, with stimulation of focal adhesion kinase (FAK) and paxillin. This detailed understanding of the ‘biochemical signature’ of N and S cells provides the background needed to target and disrupt specific IGF signaling pathways in an attempt to develop more effective therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 9
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Anderson DJ . (1993). Annu. Rev. Neurosci., 16, 129–158.

  • Baltensperger K, Kozma LM, Cherniack AD, Klarlund JK, Chawla A, Banerjee U and Czech MP . (1993). Science, 260, 1950–1952.

  • Baserga R . (1995). Cancer Res., 55, 249–252.

  • Bellis SL, Miller JT and Turner CE . (1995). J. Biol. Chem., 270, 17437–17441.

  • Biedler JL, Helson L and Spengler BA . (1973). Cancer Res., 33, 2643–2652.

  • Biedler JL, Spengler BA, Tien-ding C and Ross RA . (1988). Adv. Neuroblastoma Res., 2, 265–276.

  • Brodeur GM . (2003). Nat. Rev. Cancer, 3, 203–216.

  • Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH and Pollak M . (1998). Science, 279, 563–566.

  • Cheatham B and Kahn CR . (1995). Endocr. Rev., 16, 117–142.

  • Cheng H-L, Steinway M, Delaney CL, Franke TF and Feldman EL . (2000). Mol. Cell. Endocrinol., 170, 211–215.

  • Ciccarone V, Spengler BA, Meyers MB, Biedler JL and Ross RA . (1989). Cancer Res., 49, 219–225.

  • Corvi R, Savelyeva L and Schwab M . (1997). J. Neurooncol., 31, 25–31.

  • DeClerck YA, Bomann ET, Spengler BA and Biedler JL . (1987). Cancer Res., 47, 6505–6510.

  • De Meyts P, Wallach B, Christoffersen CT, Urso B, Gronskov K, Latus L-J, Yakushiji F, Ilondo MM and Shymko RM . (1994). Horm. Res., 42, 152–169.

  • Devary Y, Gottlieb RA, Smeal T and Karin M . (1992). Cell, 71, 1081–1091.

  • Encinas M, Iglesias M, Llecha N and Comella JX . (1999). J. Neurochem., 73, 1409–1421.

  • Favrot MC, Combaret V, Goillot E, Lutz P, Frappaz D, Thiesse P, Thyss A, Dolbeau D, Bouffet E and Tabone E . (1991). Int. J. Cancer, 49, 347–355.

  • Feldman EL, Sullivan KA, Kim B and Russell JW . (1997). Neurobiol. Dis., 4, 201–214.

  • Flickinger KS, Judware R, Lechner R, Carter WG and Culp LA . (1994). Exp. Cell Res., 213, 156–163.

  • Franke TF, Kaplan DR and Cantley LC . (1997). Cell, 88, 435–437.

  • Frappaz D, Michon J, Coze C, Berger C, Plouvier E, Lasset C, Bernard JL, Stephan JL, Bouffet E, Buclon M, Combaret V, Fourquet A, Philip T and Zucker JM . (2000). J. Clin. Oncol., 18, 468–476.

  • Giancotti FG and Ruoslahti E . (1999). Science, 285, 1028–1032.

  • Giorgetti S, Pelicci PG, Pelicci G and Van Obberghen E . (1994). Eur. J. Biochem., 223, 195–202.

  • Greene MW, Sakaue H, Wang L, Alessi DR and Roth RA . (2003). J. Biol. Chem., 278, 8199–8211.

  • Guo HB, Lee I, Kamar M, Akiyama SK and Pierce M . (2002). Cancer Res., 62, 6837–6845.

  • Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE and Pollak M . (1998). Lancet, 351, 1393–1396.

  • Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM and Kobayashi M . (2000). Mol. Endocrinol., 14, 783–794.

  • Hood JD and Cheresh DA . (2002). Nat. Rev. Cancer, 2, 91–100.

  • Ivankovic-Dikic I, Gronroos E, Blaukat A, Barth BU and Dikic I . (2000). Nat. Cell Biol., 2, 574–581.

  • Judware R and Culp LA . (1995). Oncogene, 11, 2599–2607.

  • Kim B, Cheng H-L, Margolis B and Feldman EL . (1998a). J. Biol. Chem., 273, 34543–34550.

  • Kim B and Feldman EL . (1998). J. Neurochem., 71, 1333–1336.

  • Kim B and Feldman EL . (2002). J. Biol. Chem., 277, 27393–27400.

  • Kim B, Leventhal PS, Saltiel AR and Feldman EL . (1997). J. Biol. Chem., 272, 21268–21273.

  • Kim B, Leventhal PS, White MF and Feldman EL . (1998b). Endocrinology, 139, 4881–4889.

  • Kurihara S, Hakuno F and Takahashi S . (2000). Endocr. J., 47, 739–751.

  • Lebrun P, Mothe-Satney I, Delahaye L, Van Obberghen E and Baron V . (1998). J. Biol. Chem., 273, 32244–32253.

  • Leventhal PS and Feldman EL . (1997). Trends Endocrinol. Metab., 8, 1–6.

  • Leventhal PS, Shelden EA, Kim B and Feldman EL . (1997). J. Biol. Chem., 272, 5214–5218.

  • Liu X, Turbyville T, Fritz A and Whitesell L . (1998). Cancer Res., 58, 5432–5438.

  • Meyer G and Feldman EL . (2002). J. Neurochem., 83, 490–503.

  • Meyer GE, Shelden E, Kim B and Feldman EL . (2001). Oncogene, 20, 7542–7550.

  • Miller TM, Tansey MG, Johnson Jr EM and Creedon DJ . (1997). J. Biol. Chem., 272, 9847–9853.

  • Myers Jr MG and White MF . (1996). Annu. Rev. Pharmacol. Toxicol., 36, 615–658.

  • Ogihara T, Shin BC, Anai M, Katagiri H, Inukai K, Funaki M, Fukushima Y, Ishihara H, Takata K, Kikuchi M, Yazaki Y, Oka Y and Asano T . (1997). J. Biol. Chem., 272, 12868–12873.

  • Parsons JT . (2003). J. Cell Sci., 116, 1409–1416.

  • Pederson TM, Kramer DL and Rondinone CM . (2001). Diabetes, 50, 24–31.

  • Pronk GJ, McGlade J, Pelicci G, Pawson T and Bos JL . (1993). J. Biol. Chem., 268, 5748–5753.

  • Reiss K, D'Ambrosio C, Tu X, Tu C and Baserga R . (1998). Clin. Cancer Res., 4, 2647–2655.

  • Reiss K, Wang JY, Romano G, Furnari FB, Cavenee WK, Morrione A, Tu X and Baserga R . (2000). Oncogene, 19, 2687–2694.

  • Rettig WJ, Spengler BA, Chesa PG, Old LJ and Biedler JL . (1987). Cancer Res., 47, 1383–1389.

  • Ross RA and Biedler JL . (1985). Cancer Res., 45, 1628–1632.

  • Ross RA, Spengler BA, Domenech C, Porubcin M, Rettig WJ and Biedler JL . (1995). Cell Growth Differ., 6, 449–456.

  • Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, Dunaif A and White MF . (2001a). J. Clin. Invest., 107, 181–189.

  • Rui L, Fisher TL, Thomas J and White MF . (2001b). J. Biol. Chem., 276, 40362–40367.

  • Russell JW, Windebank AJ, Schenone A and Feldman EL . (1998). J. Neurobiol., 36, 455–467.

  • Salgia R, Li JL, Ewaniuk DS, Wang YB, Sattler M, Chen WC, Richards W, Pisick E, Shapiro GI, Rollins BJ, Chen LB, Griffin JD and Sugarbaker DJ . (1999). Oncogene, 18, 67–77.

  • Sarbassov DD and Peterson CA . (1998). Mol. Endocrinol., 12, 1870–1878.

  • Sasaoka T, Langlois WJ, Leitner JW, Draznin B and Olefsky JM . (1994). J. Biol. Chem., 269, 32621–32625.

  • Schaller MD . (2001). Oncogene, 20, 6459–6472.

  • Schmidt ML, Lukens JN, Seeger RC, Brodeur GM, Shimada H, Gerbing RB, Stram DO, Perez C, Haase GM and Matthay KK . (2000). J. Clin. Oncol., 18, 1260–1268.

  • Scibelli A, D'Angelo D, Pelagalli A, Tafuri S, Avallone L, Morte RD and Staiano N . (2003). Vet. Res., 34, 193–202.

  • Seiler AE, Ross BN and Rubin R . (2001). J. Neurochem., 76, 573–581.

  • Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH and Schlaepfer DD . (2000). Nat. Cell Biol., 2, 249–256.

  • Singleton JR, Randolph AE and Feldman EL . (1996). Cancer Res., 56, 4522–4529.

  • Thomas JW, Cooley MA, Broome JM, Salgia R, Griffin JD, Lombardo CR and Schaller MD . (1999). J. Biol. Chem., 274, 36684–36692.

  • Tumilowicz JJ, Nichols WW, Cholon JJ and Greene AE . (1970). Cancer Res., 30, 2110–2118.

  • Valentinis B, Navarro M, Zanocco-Marani T, Edmonds P, McCormick J, Morrione A, Sacchi A, Romano G, Reiss K and Baserga R . (2000). J. Biol. Chem., 275, 25451–25459.

  • Valentinis B, Romano G, Peruzzi F, Morrione A, Prisco M, Soddu S, Cristofanelli B, Sacchi A and Baserga R . (1999). J. Biol. Chem., 274, 12423–12430.

  • van Golen CM and Feldman EL . (2000). J. Cell. Physiol., 182, 24–32.

  • van Golen CM, Schwab TS, Woods Ignatoski KM, Ethier SP and Feldman EL . (2001). Cell Growth Differ., 12, 371–378.

  • Vincent AM and Feldman EL . (2002). Growth Horm. IGF Res., 12, 193.

  • Waters SB and Pessin JE . (1996). Trends Cell Biol., 6, 1–4.

  • Yee D . (2002). Semin. Oncol., 29, 86–95.

  • Yoshihara T, Esumi N, Humphries MJ and Imashuku S . (1992). Int. J. Cancer, 51, 620–626.

  • Yu H, Spitz MR, Mistry J, Gu J, Hong WK and Wu X . (1999). J. Natl. Cancer Inst., 91, 151–156.

  • Zumkeller W and Schwab M . (1999). Horm. Metab. Res., 31, 138–141.

Download references

Acknowledgements

We thank Ms Judith Boldt for expert secretarial assistance. This work was supported by the National Institutes of Health (NS36778, NS38849) and the Program for Understanding Neurological Diseases (PFUND).

Author information

Authors and Affiliations

  1. Department of Neurology, University of Michigan, 4414 Kresge III, 200 Zina Pitcher Place, Ann Arbor, 48109-0588, MI, USA

    Bhumsoo Kim, Cynthia M van Golen & Eva L Feldman

Authors
  1. Bhumsoo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cynthia M van Golen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eva L Feldman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bhumsoo Kim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, B., van Golen, C. & Feldman, E. Insulin-like growth factor-I signaling in human neuroblastoma cells. Oncogene 23, 130–141 (2004). https://doi.org/10.1038/sj.onc.1206924

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206924

Keywords

This article is cited by

Search

Advanced search

Quick links