Figure 1
Insulin/IGF receptor binding. As tyrosine kinase receptors, the IR and the IGF receptors, consist of an extracellular ligand-binding domain and a cytosolic tyrosine kinase domain that autophosphorylates upon ligand binding and transphosphorylates several substrates that initiate downstream signaling. The IR shares ~50 and 80% homology with the ligand-binding and tyrosine kinase domain, respectively, of the IGF-1 receptor (IGF-1R).30 It exists in two isoforms, IR-A and IR-B, which promote either mainly mitogenic or metabolic effects, depending on the ligand and the cellular context, allowing cells flexibility in responding to mainly one or the other stimulus. In general, IR-A is preferentially associated with mitogenic and anti-apoptotic signaling, whereas IR-B is associated with cell differentiation and metabolic effects.30 A predominant expression of IR-A has correspondingly been found in fetal tissue and tumors with autocrine production of IGF-2, which binds this receptor with 30–40% affinity compared with insulin.210 In this way, these tumors promote cell proliferation in an autocrine manner.30, 211 IGF-2 also binds to the IGF-1R, whereas IGF-1 binds to its own IGF-1R and to hybrid receptors of IGF-1R and IR-A as well as IGF-1R and IR-B.30, 212 Physiological concentrations of insulin show no measurable binding to the IGF-1R both in vitro30 and in vivo.213 Nevertheless, in mammals, insulin may be the major controller of insulin/IGF-1 action due to its effect on the bioavailability of IGF-1.43
