Exp Clin Endocrinol Diabetes 1996; 104: 17-18
DOI: 10.1055/s-0029-1211501
Part II — Oral Presentations
Receptor Structure & Function II
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

O-10: Mutant insulin receptors Arg1174Gln and Pro1178Leu — naturally occurring insulin receptor mutations as tools in the dissection of insulin signal transduction pathways

A. Krook1 , D. M. Ouwens2 , D. E. Moller3 , J. A. Maassen2 , S. O'Rahilly1
  • 1Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Cambridge, England
  • 2Department of Medical Biochemistry, Sylvius Laboratories, Leiden University, Leiden, The Netherlands
  • 3Merck Research Laboratories, Rahway, New Jersey, USA
Further Information

Publication History

Publication Date:
15 July 2009 (online)

Summary

Naturally occurring insulin receptor mutations, identified in patients suffering from insulin resistant syndromes have often acted as “experiments of nature”, giving valuable insights into the structure function relationship of insulin signalling. We report on the unique functional properties of two naturally occurring mutants in a region of the insulin receptor tyrosine kinase domain distal to the major sites of tyrosine auto-phosphorylation. The mutations are the cause of dominantly-inherited resistance to insulin-mediated glucose disposal in vivo. Both mutations result in the abolition of insulin-stimulated receptor auto-phosphorylation but retention of insulin-stimulated IRS1 tyrosine-phosphorylation. Phosphorylation of the downstream target She was also severely impaired in these cells. Despite mediating apparently normal IRS1 phosphorylation, neither mutant insulin receptor was capable of stimulating metabolic and mitogenic events. These results lend support to the notion that IRS 1-independent signalling ev-cents are necessary for the mediation of the downstream effects of insulin. The unique properties of these receptors also allows the dissection of the relative roles of different downstream mediators in insulin signalling.