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

✍ Scribed by Anne L. Frattali; Judith L. Treadway; Jeffrey E. Pessin

• Publisher: John Wiley and Sons
• Year: 1992
• Tongue: English
• Weight: 622 KB
• Volume: 48
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.240480108

✦ Synopsis

Classical insulin and IGF-1 receptors are azP2 heterotetrameric complexes synthesized from two identical a0 half-receptor precursors [I ,21. Recent data strongly suggests, however, that nonidentical ap half-receptor precursors can assemble to generate hybrid holoreceptor species both in vivo and in vitro [3-6,411. This review focuses primarily on two types of hybrid receptors. The first type is an insulin/lGF-I hybrid receptor generated by the association of an aP insulin half-receptor with an aP IGF-1 half-receptor. The second type is one formed from a wildtype (kinase-active) insulin or IGF-1 aP half-receptor and a mutant (kinase-inactive) insulin a@ half-receptor. Although the functional properties of insulin/lGF-1 hybrid receptors have not yet been completely defined, wildtype/mutant hybrid receptors are essentially substrate kinase inactive [6]. These data indicate that the mutant aP half-receptor exerts a transdominant inhibition upon the wildtype ap half-receptor within the a,P2 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 [ 7-1 11. In addition, cell lines which express both endogenous wi[dtype and transfected kinase-defective insulin receptors display markedly decreased insulin and IGF-1 sensitivity and responsiveness 12-1 41. 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.