title: Augmented growth response to IGF-1 via increased IRS-1 in Chinese hamster ovary cells expressing kinase-negative insulin receptors.
abstract: OBJECTIVE
  Although both increased cell growth and impaired insulin signalling have been associated with diabetes, this association has not been investigated. Insulin-like growth factor-1 (IGF-1), a structural and functional analog of insulin, may play a part in the aberrant insulin receptor-mediated signalling observed in diabetes.
  
  
  METHODS
  To investigate the consequence of this impaired signalling on cell proliferation and transformation, we transfected Chinese hamster ovary cells with cDNA encoding a kinase-defective insulin receptor.
  
  
  RESULTS
  In these mutant cells, the mitogenic and metabolic effects of insulin were reduced compared with control cells (p < 0.05) and this was due to a dominant negative effect. In contrast, these mutant cells showed a higher mitogenic response to IGF-1 than control cells, although IGF-1 receptor expression was similar in both cell lines. There was no statistically significant difference in mitogenic response, however, to platelet-derived growth factor, basic fibroblast growth factor and heparin-binding epidermal growth factor-like growth factor. Variables of the IGF-1 signalling pathway, including tyrosine phosphorylation of insulin receptor substrate-1 and activation of mitogen-activated protein kinase and phosphatidyl inositol 3 kinase, were also augmented in mutant cells. Insulin receptor substrate-1 message and protein abundance were higher in mutant than in control cells. Moreover, mutant cells had a higher mitogenic potential in low-serum-containing medium, suggesting that these cells have a transformed phenotype.
  
  
  CONCLUSIONS
  These findings suggest that an impaired insulin signalling may upregulate insulin receptor substrate-1 and that this, in turn, leads to increased IGF-1 signalling, a phenomenon that is possibly associated with increased cell growth in diabetes.
authors.affiliation: Second Department of Internal Medicine, Osaka University Medical School, Suita, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Fukuda
authors.forename: T
authors.initials: T
authors.lastname: Kudara
authors.forename: T
authors.initials: T
authors.lastname: Igura
authors.forename: Y
authors.initials: Y
authors.lastname: Inui
authors.forename: S
authors.initials: S
authors.lastname: Tamura
authors.forename: T
authors.initials: T
authors.lastname: Hanafusa
authors.forename: S
authors.initials: S
authors.lastname: Kawata
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006224:Cricetinae; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D011506:Proteins / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011506:Proteins; D055765:Shc Signaling Adaptor Proteins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D017871:Calcium-Calmodulin-Dependent Protein Kinases