Insulin-like growth factor II : Cellular effects through different receptors

Abstract: Insulin-like growth factor -II (IGF-II) and IGF-I are single-chain polypeptidesstructurally homologous to proinsulin and share similarities with insulin in functionalcharacteristics. Cellular actions of IGF-II are generally thought to be mediatedthrough the IGF-I or insulin receptors, but not the IGF-II receptor, which is a singlechain protein, identical to the cation independent mannose 6-phosphate (M6P) receptorand responsible for lysosomal enzyme targeting and degradation of IGF-II. Pancreatic ß-cells isolated from ob/ob mice were shown to have IGF-II/M6Preceptors, but not IGF-I receptors. IGF-II stimulated insulin release from ß-cellsat non-stimulatory concentrations of glucose, but inhibited glucose-induced insulinrelease. In addition, IGF-II inhibited Ca2+ -induced insulin release, but stimulatedinsulin release under basal conditions in electropermeabilized ß-cells. In contrast,IGF-I had no effect. The dual effects of IGF-II on insulin release were not associatedwith significant changes in cytoplasmic free Ca2+ concentration ([Ca2+]j). Antibodiesagainst the IGF-II/M6P receptor blocked the IGF-II action. Pretreatment of the cellswith either pertussis toxin or the phorbol ester TPA abolished the effects of IGF-II.In addition, IGF-II stimulated a PKC-dependent phosphorylation of several intracellularproteins. Thus, IGF-II, signaling through the MF Il/M6P receptor, modulated insulinexocytosis, an effect which was mediated through pertussis toxin sensitive G proteinsand was dependent on PKC activity. Glucose increased the cell surface number of IGF-II/M6P receptors in insulin secretingcells without changing the affinity for IGF-II. The glucose-induced redistributionof the IGF-II/M6P receptor was associated with an increased phosphorylation of thereceptor and was dependent on PKC activity. The glucose-induced redistribution andphosphorylation of the IGF-II/M6P receptor may play a role in IGF-II actions on insulinexocytosis. Both IGF-II and IGF-I stimulated DNA synthesis via IGF-I receptors present inthe insulin secreting cell line RlNm5F. Activation of the IGF-I receptor resultedin phosphorylation of two types of ß subunits of the receptor and the insulinreceptor substrate 2 (IRS-2), but not the insulin receptor substrate-l (IRS-I). Thespecific phosphorylation of IRS-2 in IGF-I signaling may be of significance in insulinsecreting cells. A 75 kDa protein was partially purified from the erythroleukemia cell line K562and was shown to be specific for IGF-II. In conclusion, biological actions of IGF-II can be mediated by receptors for IGF-II.The IGF-II/M6P receptor mediates the actions of IGF-II on exocytosis in insulin secretingcells. Pertussis toxin sensitive G proteins and PKC are involved in the IGF-II signaling.The IGF II induced stimulation and inhibition of insulin secretion are dependenton the glucose concentrations and glucose stimulates phosphorylation of the MF-II/M6Preceptor and redistribution of the receptor to the cell surface. In addition, IGF-II,acting through the IGF-I receptors, stimulates proliferation in the insulin secretingcell line RINm5F. The IGF-I receptor mediated cell response is associated with phosphorylationof the IGF-I receptor and IRS-2. An additional candidate as a mediator for IGF-IIaction is the 75 kDa IGF-II receptor/binding protein, which has been partially purifiedfrom K562 cells. ISBN 91-628-2754-5