title: Differential effects of insulin-like growth factor I (IGF-I) and IGF-binding protein-1 on protein metabolism in human skeletal muscle cells.
abstract: Insulin-like growth factor-binding protein-1 (BP-1) is a multifunctional protein that binds IGF-I in solution and integrins on the cell surface. BP-1 is overexpressed during catabolic illnesses, and the protein accumulates in skeletal muscle. To define a potential physiological role for BP-1 in regulating muscle protein balance, we have examined the effect of IGF-I and BP-1 on protein synthesis and degradation in human skeletal muscle cells. IGF-I-stimulated protein synthesis by 20%, and this was completely inhibited by either phosphorylated or nonphosphorylated BP-1. Half-maximal inhibition of protein synthesis occurred at a molar ratio of BP-1 to IGF-I of 1.5:1. BP-1 failed to form a complex with a truncated form of IGF-I (desIGF-I), and consequently, BP-1 failed to inhibit the ability of desIGF-I to stimulate protein synthesis. IGF-I and BP-1 dose-dependently inhibited protein degradation individually, and both BP-1 phosphovariants failed to block the ability of IGF-I to do the same. Blocking integrin receptor occupancy with the integrin antagonist echistatin blunted the ability of BP-1 to inhibit protein degradation, but had no significant effect on IGF-I-mediated changes in protein synthesis or degradation. The extracellular matrix protein vitronectin also inhibited protein degradation, but vitronectin receptor antibodies failed to block BP-1 action. In contrast, antibodies to the beta1 integrin subunit blocked BP-1-mediated inhibition of protein degradation. Rapamycin inhibited IGF-I-dependent protein synthesis, but not the ability of IGF-I to inhibit proteolysis. In contrast, rapamycin completely blocked the ability of BP-1 to inhibit proteolysis. Our results demonstrate that BP-1 inhibits IGF-I-mediated protein synthesis by binding to IGF-I. BP-1, acting independently of IGF-I, inhibits protein degradation. The IGF-independent response occurs via beta1 integrin binding and stimulation of a rapamycin-sensitive signal transduction pathway.
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey 17033, USA. rfrost@psu.edu
authors.forename: R A
authors.initials: RA
authors.lastname: Frost
authors.forename: C H
authors.initials: CH
authors.lastname: Lang
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D019012:Integrin beta1 / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D017451:Receptors, Somatomedin / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D018970:Insulin-Like Growth Factor Binding Protein 1; D019012:Integrin beta1; D036341:Intercellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D010455:Peptides; D017451:Receptors, Somatomedin; C057986:echistatin; D007334:Insulin-Like Growth Factor I; D005947:Glucose; D020123:Sirolimus; D000077191:Wortmannin