Insulin-like growth factor-I signaling in human neuroblastoma cells.
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.
Kim
Bhumsoo
B
Department of Neurology, University of Michigan, 4414 Kresge III, 200 Zina Pitcher Place, Ann Arbor, MI 48109-0588, USA. bhumsoo@umich.edu
van Golen
Cynthia M
CM
Feldman
Eva L
EL
D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016501:Neurites / Q000502:physiology; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D051419:Paxillin; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000032:analysis; D015398:Signal Transduction
D003598:Cytoskeletal Proteins; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases