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

Anne L. Frattali, Judith L. Treadway, Jeffrey E. Pessin

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Classical insulin and IGF‐1 receptors are α2β2 heterotetrameric complexes synthesized from two identical αβ half‐receptor precursors [1,2]. Recent data strongly suggests, however, that nonidentical αβ half‐receptor precursors can assemble to generate hybrid holoreceptor species both in vivo and in 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 αβ insulin half‐receptor with an αβ IGF‐1 half‐receptor. The second type is one formed from a wildtype (kinase‐active) insulin or IGF‐1 αβ half‐receptor and a mutant (kinase‐inactive) insulin αβ 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 αβ half‐receptor exerts a transdominant inhibition upon the wildtype αβ half‐receptor within the α2β2 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.

Original languageEnglish (US)
Pages (from-to)43-50
Number of pages8
JournalJournal of Cellular Biochemistry
Volume48
Issue number1
DOIs
StatePublished - Jan 1992
Externally publishedYes

Keywords

  • autophosphorylation
  • in vitro assembly
  • insulin/IGF‐1 hybrid receptors
  • protein tyrosine kinase
  • substrate phosphorylation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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