MITOGENIC PROPERTIES OF INSULIN AND INSULIN ANALOGS MEDIATED BY THE INSULIN-RECEPTOR

Insulin has traditionally been considered as a hormone essential for m etabolic regulation, while the insulin-like growth factors (IGF-I and IGF-II) are postulated to be more specifically involved in growth regu lation. The conventional wisdom is that they share each other's effect s only at high concentrations, due to their weak affinity for the hete rologous receptor. We discuss here the evidence that in the proper cel lular context, insulin can be mitogenic at physiologic concentrations through its own receptor. We studied the insulin and IGF-I binding cha racteristics of a new model suitable for analysing insulin receptor me diated mitogenesis; that is, a T-cell lymphoma line that depends on in sulin for growth, but is unresponsive to IGFs. The cells showed no spe cific binding of I-125-IGF-I and furthermore, no IGF-I receptor mRNA w as detected by RNAse protection assay in the LB cells, in contrast wit h mouse brain and thymus. The cells bound at saturation about 3000 ins ulin molecules to receptors that had normal characteristics in terms o f affinity, kinetics, pH dependence and negative co-operativity. A ser ies of insulin analogues competed for I-125-insulin binding with relat ive potencies comparable to those observed in other insulin target cel ls. The full sequence of the insulin receptor cDNA was determined and found to be identical to the published sequence of the murine insulin receptor cDNA. The LB cell line is therefore an ideal model with which to investigate insulin mitogenic signalling without interference from the IGF-I receptor. Using this model, we have started approaching the molecular basis of insulin-induced mitogenesis, in particular the rol e of signalling kinetics in choosing between mitogenic and metabolic p athways.