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

Abstract

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 aβ 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.

The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts.

“…The parent RϪ cell line has no IGF-I receptors as a consequence of targeted disruption of the IGF-I receptor gene and a low number of endogenous insulin receptors ‫ف(‬ 5,000 receptors/cell). The signaling characteristics of the transfected insulin or IGF-I receptors can therefore be investigated with essentially no background of insulin receptor/IGF-I receptor hybrids, which may otherwise mask the properties of the individual receptors (43,44).…”

Tyrosine Phosphorylation of Paxillin and Focal Adhesion Kinase during Insulin-like Growth Factor-I-stimulated Lamellipodial Advance

“…Horseradish peroxidase-conjugated goat anti-mouse and goat anti-chicken antibodies were from Vector Laboratories (Burlingame, CA). Rhodamine-phalloidin was from Molecular Probes (Eugene, OR 10,30,50,70, and 90% ethanol. The coverslips were incubated 3 times for 5 min each in 100% ethanol, followed by 5 min in hexamethyldisilazane.…”

Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti–IGF-IR antibody

“…The IGF-IR/insulin receptor heterodimeric receptor behaves more like IGF-IR than insulin receptor, exhibiting affinities for IGF-I and IGF-II similar to the IGF-IR homodimer. The heterodimeric receptor binds insulin with much lower affinity (44). To examine whether 19D12 can bind the IGF-IR/insulin receptor heterodimeric receptor and inhibit its signaling, we did immunoprecipitation experiments using 19D12 as the immunoprecipitating antibody in A2780 cells that endogenously express both IGF-IR (150,000 IGF-IR/cell) and insulin receptor (30,000 insulin receptor/cell).…”

“…2B and C). This activity is important because the presence of IGF-IR/insulin receptor heterodimers has been reported in human tumor samples and these heterodimers behave functionally similar to IGF-IR homodimers (44).…”