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

Oncogene. 2004 Jan 8;23(1):130-41. doi: 10.1038/sj.onc.1206924.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cytoskeletal Proteins / metabolism
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Humans
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / pharmacology*
  • Intracellular Signaling Peptides and Proteins
  • Mitogen-Activated Protein Kinases / physiology
  • Neurites / physiology
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Paxillin
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoproteins / analysis
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Receptor, IGF Type 1 / analysis
  • Signal Transduction*


  • Cytoskeletal Proteins
  • IRS1 protein, human
  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • PXN protein, human
  • Paxillin
  • Phosphoproteins
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Receptor, IGF Type 1
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • PTK2 protein, human
  • Mitogen-Activated Protein Kinases