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Effects of somatic mutations in the C-terminus of insulin-like growth factor 1 receptor on activity and signaling

Barbara P Craddock1, W Todd Miller

  • 1Department of Physiology and Biophysics, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.

Journal of Signal Transduction
|July 11, 2012
PubMed

Insights

Three novel insulin-like growth factor I receptor (IGF1R) mutations found in cancer do not alter kinase activity but increase MAP kinase and Akt signaling. These findings suggest altered protein interactions may drive enhanced IGF1R signaling in cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The insulin-like growth factor I receptor (IGF1R) is frequently overexpressed in various human cancers.
  • IGF1R is a validated target for anticancer drug development.
  • Recent cancer genome sequencing identified three specific somatic mutations in IGF1R: A1374V, S1278 deletion, and M1255I.

Purpose of the Study:

  • To investigate the functional impact of three identified IGF1R somatic mutations.
  • To assess the effects of these mutations on IGF1R biochemical activity and downstream signaling pathways.

Main Methods:

  • In vitro biochemical assays to measure IGF1R tyrosine kinase activity.
  • Mammalian cell-based assays to analyze MAP kinase and Akt activation.
  • Comparison of mutant IGF1R activity against wild-type IGF1R.

Main Results:

  • The A1374V, S1278 deletion, and M1255I mutations did not affect the intrinsic tyrosine kinase activity of IGF1R.
  • Mutant IGF1R exhibited increased basal activation of MAP kinase and Akt signaling pathways compared to wild-type IGF1R.
  • These results suggest altered protein-protein interactions involving the IGF1R C-terminus.

Conclusions:

  • The identified IGF1R mutations enhance downstream signaling (MAPK and Akt) without altering intrinsic kinase function.
  • Altered protein-protein interactions are hypothesized to mediate the increased signaling potential of these cancer-associated IGF1R mutants.
  • These findings provide insights into novel mechanisms of IGF1R dysregulation in cancer.

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