Timing-dependence of insulin-receptor mitogenic versus metabolic signalling: a plausible model based on coincidence of hormone and effector binding

Mitogenic signalling through the insulin receptor is enhanced compared with metabolic signalling for insulin analogues, having slower dissociation kin etics than insulin itself. A plausible explanation in molecular terms of th is timing-dependent specificity is lacking. We show here that if signalling is transmitted through a single effector, binding coincidentally with horm one to the insulin receptor and whose association and dissociation kinetics are slow relative to the hormone dissociation rate, the resulting biologic al effect is predicted to be dependent on hormone-binding kinetics. However , known primary effector molecules associating with the insulin receptor bi nd and interact rapidly with the receptor, contrary to the assumptions of t he single-effector model. A model with two effecters which must bind coinci dentally with hormone for signalling to occur also gives the required depen dence of signalling on hormone-binding kinetics, provided that at least one of the effecters has slow binding kinetics relative to hormone binding. In this case, the other effector can have rapid kinetics, which is consistent with the properties of the major known substrates of the insulin receptor, such as the insulin receptor substrate (IRS) molecules.