Insulin/IGF‐1 hybrid receptors: Implications for the dominant‐negative phenotype in syndromes of insulin resistance

Abstract

Classical insulin and IGF-1 receptors are alpha 2 beta 2 heterotetrameric complexes synthesized from two identical alpha beta half-receptor precursors. Recent data strongly suggests, however, that nonidentical alpha beta half-receptor precursors can assemble to generate hybrid holoreceptor species both in vivo and in vitro. This review focuses primarily on two types of hybrid receptors. The first type is an insulin/IGF-1 hybrid receptor generated by the association of an alpha beta insulin half-receptor with an alpha beta IGF-1 half-receptor. The second type is one formed from a wildtype (kinase-active) insulin or IGF-1 alpha beta half-receptor and a mutant (kinase-inactive) insulin alpha beta half-receptor. Although the functional properties of insulin/IGF-1 hybrid receptors have not yet been completely defined, wildtype/mutant hybrid receptors are essentially substrate kinase inactive. These data indicate that the mutant alpha beta half-receptor exerts a transdominant inhibition upon the wildtype alpha beta half-receptor within the alpha 2 beta 2 holoreceptor complex. This defect in substrate kinase activity may contribute to the molecular defect underlying some syndromes of severe insulin resistance and diabetes. Heterozygous individuals expressing both wildtype and mutant tyrosine kinase-defective insulin receptor precursors demonstrate varying degrees of insulin resistance and diabetes. In addition, cell lines which express both endogenous wildtype and transfected kinase-defective insulin receptors display markedly decreased insulin and IGF-1 sensitivity and responsiveness. Formation of hybrid receptors which results in premature termination of insulin signal transduction may be one mechanism underlying the observation that kinase-inactive receptors inhibit the function of native receptors.

Functional properties of a heterozygous mutation (Arg1174 → Gln) in the tyrosine kinase domain of the insulin receptor from a Type A insulin resistant patient

“…This interpretation is consistent with the observation that most of those kinase mutations are inherited as a dominant trait [9,10,31,32,38]. Furthermore, the in vitro assembly of kinase defective receptor halves with wt receptor halves also results in a dominant inhibition of the kinase activity [41,42].…”

Protein kinases — structure and function

“…Apparently, 'self' binding of the activation loop transmits serious distortions to the DFG motif. Hubbard et al suggest trans-autophosphorylation dislodges the autoinhibitory loop, in agreement with biochemical findings [28,29].…”

CSF-1 Receptor/Insulin Receptor Chimera Permits CSF-1-dependent Differentiation of 3T3-L1 Preadipocytes

“…Activation of the tyrosine kinases encoded by these receptors is believed to require ligand-induced dimerization of two identical receptor proteins (26). Activation of the insulin receptor tyrosine kinase in the chimera may result from CSF-1-induced dimerization of the CSF1R/IR protein that permits trans-phosphorylation of juxtaposed tyrosine kinase domains (27). These observations suggest that the proper orientation of juxtaposed tyrosine kinase domains is sufficient for the activation of tyrosine kinase activity.…”