Molecular dynamics of insulin/IGF‐I receptor transmembrane signaling

Jeffrey E. Pessin, Anne L. Frattali

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

To examine the molecular basis of ligand‐stimulated intramolecular β‐subunit autophosphorylation, hybrid receptors composed of wild‐type and mutantinsulin and insulin‐like growth factor‐1 (lGF‐l) half‐receptor precursors were characterized. Previous studies have demonstrated that assembly of the IGF‐I wild‐type half‐receptor (αβWT) with a kinase‐defective half‐receptor (αβA/K) produced a substrate kinase‐inactive holoreceptor in vitro [Treadway et al. (1991): Proc Natl Acad Sci USA 88:214–218]. To extend these studies, the vaccinia virus/ bacteriophage T7 expression system was used to generate various hybrid receptor complexes in cultured cells. As was observed for hybrid receptors assembled in vitro, the wild‐type/mutant hybrid receptors formed in situ were also incapable of phosphorylating several peptide substrates. However, ligand‐stimulated β‐subunit autophosphorylation was still observed. To determine the molecular basis for this discrepancy, hybrid receptors were assembled from a truncated β‐subunit insulin half‐receptor (αβδ43). and a kinase‐defective half‐receptor (αβA/K). Under these conditions, insulin‐stimulated autophosphorylation primarily oc‐curred on the full‐length kinase‐inactive β‐subunit (αβA/K) without significant labeling of the kinase‐active truncated β‐subunit (αβδ43). A similar IGF‐I hybrid receptor species was characterized, and the same pattern of autophosphorylation was observed in response to IGF‐I. These data demonstrate that both insulin and IGF‐I stimulate an intramolecular trans‐autophosphorylation reaction between two adjacent β‐subunits within the holoreceptors. Furthermore, our data suggest that trans‐phosphorylation between two functional β‐subunits is required for substrate kinase activation of the insulin and IGF‐I holoreceptors. These results suggest a molecular basis for the dominant‐negative phenotype observed in heterozygous, insulin‐resistant patients possessing one kinase‐defective insulin receptor allele. © 1993 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)339-345
Number of pages7
JournalMolecular Reproduction and Development
Volume35
Issue number4
DOIs
Publication statusPublished - Aug 1993
Externally publishedYes

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Keywords

  • Auto‐phosphorylation
  • Hybrid receptors
  • Kinase
  • β‐subunit

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology
  • Cell Biology

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