title: Identification of insulin receptor substrate proteins as key molecules for the TbetaR-V/LRP-1-mediated growth inhibitory signaling cascade in epithelial and myeloid cells.
abstract: The type V TGF-beta receptor (TbetaR-V) mediates IGF-independent growth inhibition by IGFBP-3 and mediates growth inhibition by TGF-beta1 in concert with the other TGF-beta receptor types. TbetaR-V was recently found to be identical to LRP-1. Here we find that insulin and (Q3A4Y15L16) IGF-I (an IGF-I analog that has a low affinity for IGFBP-3) antagonize growth inhibition by IGFBP-3 in mink lung epithelial cells (Mv1Lu cells) stimulated by serum. In these cells, IGFBP-3 induces serine-specific dephosphorylation of IRS-1 and IRS-2. The IGFBP-3-induced dephosphorylation of IRS-2 is prevented by cotreatment of cells with insulin, (Q3A4Y15L16) IGF-I, or TbetaR-V/LRP-1 antagonists. The magnitude of the IRS-2 dephosphorylation induced by IGFBP-3 positively correlates with the degree of growth inhibition by IGFBP-3 in Mv1Lu cells and mutant cells derived from Mv1Lu cells. Stable transfection of murine 32D myeloid cells (which lack endogenous IRS proteins and are insensitive to growth inhibition by IGFBP-3) with IRS-1 or IRS-2 cDNA confers sensitivity to growth inhibition by IGFBP-3; this IRS-mediated growth inhibition can be completely reversed by insulin in 32D cells stably expressing IRS-2 and the insulin receptor. These results suggest that IRS-1 and IRS-2 are key molecules for the TbetaR-V/LRP-1-mediated growth inhibitory signaling cascade.
authors.affiliation: Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1402 South Grand Boulevard St. Louis, MO 63104, USA. huangss@slu.edu
authors.forename: Shuan Shian
authors.initials: SS
authors.lastname: Huang
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Leal
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Chen
authors.forename: I-Hua
authors.initials: IH
authors.lastname: Liu
authors.forename: Jung San
authors.initials: JS
authors.lastname: Huang
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D006131:Growth Inhibitors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010750:Phosphoproteins; D018125:Receptors, Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I