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.
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.
Huang
Shuan Shian
SS
Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1402 South Grand Boulevard St. Louis, MO 63104, USA. huangss@slu.edu
Leal
Sandra M
SM
Chen
Chun-Lin
CL
Liu
I-Hua
IH
Huang
Jung San
JS
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
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