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

Abstract

Insulin-like growth factor-II (IGF-II) and IGF-I are single-chain polypeptides structurally homologous to proinsulin and share similarities with insulin in functional characteristics. Cellular actions of IGF-II are generally thought to be mediated through the IGF-I or insulin receptors, but not the IGF-II receptor, which is a single chain protein, identical to the cation independent mannose 6-phosphate (M6P) receptor and responsible for lysosomal enzyme targeting and degradation of IGF-II.

Pancreatic ß-cells isolated from ob/ob mice were shown to have IGF-II/M6 Preceptors, but not IGF-I receptors. IGF-II stimulated insulin release from ß-cells at non-stimulatory concentrations of glucose, but inhibited glucose-induced insulin release. In addition, IGF-II inhibited Ca2+ -induced insulin release, but stimulated insulin 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 associated with significant changes in cytoplasmic free Ca2+ concentration ([Ca2+]j). Antibodies against the IGF-II/M6P receptor blocked the IGF-II action. Pretreatment of the cells with 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 intracellular proteins. Thus, IGF-II, signaling through the MF Il/M6P receptor, modulated insulin exocytosis, an effect which was mediated through pertussis toxin sensitive G proteins and was dependent on PKC activity.

Glucose increased the cell surface number of IGF-II/M6P receptors in insulin secreting cells without changing the affinity for IGF-II. The glucose-induced redistribution of the IGF-II/M6P receptor was associated with an increased phosphorylation of the receptor and was dependent on PKC activity. The glucose-induced redistribution and phosphorylation of the IGF-II/M6P receptor may play a role in IGF-II actions on insulin exocytosis.

Both IGF-II and IGF-I stimulated DNA synthesis via IGF-I receptors present in the insulin secreting cell line RlNm5F. Activation of the IGF-I receptor resulted in phosphorylation of two types of ß subunits of the receptor and the insulin receptor substrate 2 (IRS-2), but not the insulin receptor substrate-l (IRS-I). The specific phosphorylation of IRS-2 in IGF-I signaling may be of significance in insulin secreting cells. A 75 kDa protein was partially purified from the erythroleukemia cell line K562 and 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 secreting cells. 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 dependent on the glucose concentrations and glucose stimulates phosphorylation of the MF-II/M6. Preceptor and redistribution of the receptor to the cell surface. In addition, IGF-II, acting through the IGF-I receptors, stimulates proliferation in the insulin secreting cell line RINm5F. The IGF-I receptor mediated cell response is associated with phosphorylation of the IGF-I receptor and IRS-2. An additional candidate as a mediator for IGF-II action is the 75 kDa IGF-II receptor/binding protein, which has been partially purified from K562 cells.