INSULIN IGF-1 HYBRID RECEPTORS - IMPLICATIONS FOR THE DOMINANT-NEGATIVE PHENOTYPE IN SYNDROMES OF INSULIN RESISTANCE

被引:51
作者
FRATTALI, AL [1 ]
TREADWAY, JL [1 ]
PESSIN, JE [1 ]
机构
[1] UNIV IOWA,DEPT PHYSIOL & BIOPHYS,IOWA CITY,IA 52242
关键词
INSULIN IGF-1 HYBRID RECEPTORS; AUTOPHOSPHORYLATION; SUBSTRATE PHOSPHORYLATION; PROTEIN TYROSINE KINASE; INVITRO ASSEMBLY;
D O I
10.1002/jcb.240480108
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Classical insulin and IGF-1 receptors are alpha(2)beta(2) heterotetrameric complexes synthesized from two identical alpha-beta-half-receptor precursors [1,2]. Recent data strongly suggests, however, that nonidentical alpha-beta-half-receptor precursors can assemble to generate hybrid holoreceptor species both in vivo and vitro [3-6,41]. 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 [6]. 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 [7-11]. 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 [12-14]. 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.
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页码:43 / 50
页数:8
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