Transmembrane signaling by the human insulin receptor kinase. Relationship between intramolecular β subunit trans- and cis-autophosphorylation and substrate kinase activation

A. L. Frattali, J. L. Treadway, J. E. Pessin

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Abstract

To examine the role of intramolecular β subunit trans- and cis- autophosphorylation in signal transduction, the vaccinia virus/bacteriophage T7 expression system was used to generate insulin holoreceptors composed of a kinase-defective half-receptor precursor (αβ(A/K) or αβ(A/K.ΔCT)) and a kinase-active half-receptor precursor (αβ(ΔCT) or αβ(WT)). In the αβ(A/K)-αβ(ΔCT) hybrid insulin receptor, insulin stimulated a 20-fold increase in intramolecular β subunit trans-phosphorylation, whereas cis- phosphorylation increased only 3-fold over the basal state. Similarly, in the αβ(WT)-αβ(A/K.ΔCT) hybrid insulin receptor, insulin stimulated trans- phosphorylation approximately 30-fold and cis-phosphorylation only 3-fold over the basal state. Although cis-phosphorylation of the kinase-functional αβ half-receptor was observed within these hybrid receptor species, this was not sufficient to stimulate exogenous substrate kinase activity. These data demonstrate that insulin primarily activates an intramolecular β subunit trans-phosphorylation reaction within the insulin holoreceptor and suggest that this reaction is necessary for activation of the holoreceptors. Furthermore, our results suggest a molecular basis for the dominant-negative phenotype observed in insulin-resistant patients possessing one kinase- defective insulin receptor allele.

Original languageEnglish (US)
Pages (from-to)19521-19528
Number of pages8
JournalJournal of Biological Chemistry
Volume267
Issue number27
Publication statusPublished - Jan 1 1992
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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