title: The pro-forms of insulin-like growth factor I (IGF-I) are predominant in skeletal muscle and alter IGF-I receptor activation.
abstract: IGF-I is a key regulator of muscle development and growth. The pre-pro-peptide produced by the Igf1gene undergoes several posttranslational processing steps to result in a secreted mature protein, which is thought to be the obligate ligand for the IGF-I receptor (IGF-IR). The goals of this study were to determine what forms of IGF-I exist in skeletal muscle, and whether the mature IGF-I protein was the only form able to activate the IGF-IR. We measured the proportion of IGF-I species in murine skeletal muscle and found that the predominant forms were nonglycosylated pro-IGF-I and glycosylated pro-IGF-I, which retained the C-terminal E peptide extension, instead of mature IGF-I. These forms were validated using samples subjected to viral expression of IGF-I combined with furin and glycosidase digestion. To determine whether the larger molecular weight IGF-I forms were also ligands for the IGF-IR, we generated each specific form through transient transfection of 3T3 cells and used the enriched media to perform kinase receptor activation assays. Compared with mature IGF-I, nonglycosylated pro-IGF-I had similar ability to activate the IGF-IR, whereas glycosylation of pro-IGF-I significantly reduced receptor activation. Thus, it is important to understand not only the quantity, but also the proportion of IGF-I forms produced, to evaluate the true biological activity of this growth factor.
authors: Department of Anatomy and Cell Biology, School of Dental Medicine, and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Julia
authors: J
authors: Durzyńska
authors: Anastassios
authors: A
authors: Philippou
authors: Becky K
authors: BK
authors: Brisson
authors: Michelle
authors: M
authors: Nguyen-McCarty
authors: Elisabeth R
authors: ER
authors: Barton
mesh_terms: D016475:3T3 Cells; D000818:Animals; D045683:Furin / Q000378:metabolism; D006031:Glycosylation; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D018482:Muscle, Skeletal / Q000378:metabolism*; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D011498:Protein Precursors; D011994:Recombinant Proteins; C119953:pro-insulin-like growth factor I; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D045683:Furin