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The Nature and Regulation of the Receptors for Insulin-Like Growth Factors

1985; Annual Reviews; Volume: 47; Issue: 1 Linguagem: Inglês

10.1146/annurev.ph.47.030185.002233

1545-1585

Matthew M. Rechler, S. Peter Nissley,

Protein Kinase Regulation and GTPase Signaling

Two subtypes of IGF receptors have been identified. Type I IGF receptors have a Mr greater than 300,000 and are composed of disulfide-linked 130,000-dalton (alpha) and approximately 90,000-dalton (beta) subunits. The alpha subunit binds hormone; the beta subunit appears to have intrinsic tyrosine kinase activity and to be autophosphorylated. Type I receptors preferentially bind IGF-I but also bind IGF-II and, more weakly, insulin. Type II IGF receptors consist of a 250,000-dalton protein that contains internal disulfide bonds but is not linked to other membrane components. Type II receptors bind IGF-II with higher affinity than IGF-I. They do not interact with even very high concentrations of insulin. Type I IGF receptors and insulin receptors are homologous structures. They have similar subunit structure. Both receptors bind IGFs and insulin. They have similar (but not identical) antigenic determinants. Both receptors are downregulated by IGFs and insulin. Both receptors are affected in certain patients with genetically determined insulin resistance. Type II IGF receptors do not appear to be homologous to type I receptors. They differ in structure, peptide binding specificity, and antigenic determinants. Type II receptors do not appear to be downregulated. Although type II receptors appear to be phosphorylated in intact cells, they do not possess intrinsic tyrosine protein-kinase activity. Insulin acutely upregulates type II IGF receptors in intact rat adipose cells by effecting a redistribution of receptors cycling between a large intracellular pool and the plasma membrane. Insulin and the IGFs elicit the same biological responses, either by cross-reacting with one of the receptors for the heterologous ligand or by concurrent activation of convergent effector pathways by binding to the homologous receptor. Which mechanism is utilized appears to depend more on the tissue than on the biological response. Insulin desensitizes rat hepatoma cells to the actions of insulin and IGFs, mediated by both insulin and IGF receptors, by mechanisms distal to hormone binding and possibly common to IGF and insulin effector pathways.