Barbara T. Navé

Hybrid and Atypical Insulin/lnsulin-Like Growth Factor I Receptors

The insulin receptor and type 1 insulin-like growth factor (IGF) receptor as classically described are each the product of a single gene. Various receptor subtypes have been described, however, with distinct structures or binding properties. Two of these subtypes have been studied, namely hybrid and atypical IGF-I receptors. Hybrid receptors contain alpha beta halves of both the insulin and the IGF receptor. They are identifiable as a high-affinity IGF-I-binding species reacting with both IGF-receptor-specific and insulin-receptor-specific monoclonal antibodies, and account for a substantial fraction of IGF receptor in many mammalian tissues. Hybrid receptors purified from human placenta bind IGF-I with approximately 25-fold higher affinity than insulin, the affinity for insulin being 10-fold less than that of the classical insulin receptor. It is therefore likely that hybrids will respond more readily to IGF-I than to insulin in vivo. Atypical IGF receptors are characterized by an ability to bind insulin as well as IGFs with relatively high affinity, but are immunologically indistinguishable from classical IGF receptor and do not react with insulin receptor-specific antibodies. The structural basis of atypical binding behaviour is unknown, though the effect is mimicked by binding of certain anti-IGF receptor monoclonal antibodies, which dramatically increase the affinity of the IGF receptor for insulin. Specific physiological roles have not been demonstrated for hybrid or atypical receptors, but the available information concerning their distribution and properties suggests that these receptor subtypes may have an important influence on the specificity of action of insulin and IGFs in vivo.

Immunological Studies of Type I IGF Receptors and Insulin Receptors: Characterisation of Hybrid and Atypical Receptor Subtypes

The insulin receptor (IR) and type I IGF receptor (IGFR) are widely distributed in mammalian tissues, though varying in concentration between different cell types. The receptors show considerable similarity in primary sequence within a common disulphide linked (αβ)2 subunit structure. The insulin receptor-related receptor (IRR), a third member of this receptor family for which a ligand has yet to be identified, apparently has a much more restricted tissue distribution (Shier and Watt, 1992). The IR and IGFR mediate overlapping biological responses for which the intrinsic tyrosine-specific kinase activity of the receptors appears to be essential. These tyrosine kinases are highly homologous and differences in signalling capacities of the IR and IGFR in a given cell background have not been clearly defined.