Effects of Somatic Mutations in the C-Terminus of Insulin-Like Growth Factor 1 Receptor on Activity and Signaling.pdfVIP

Hindawi Publishing Corporation Journal of Signal Transduction Volume 2012, Article ID 804801, 7 pages doi:10.1155/2012/804801 Research Article Effects of Somatic Mutations in the C-Terminus of Insulin-Like Growth Factor 1 Receptor on Activity and Signaling Barbara P. Craddock and W. Todd Miller Department of Physiology and Biophysics, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA Correspondence should be addressed to W. Todd Miller, ler@ Received 7 March 2012; Accepted 28 April 2012 Academic Editor: A. Yoshimura Copyright © 2012 B. P. Craddock and W. T. Miller. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The insulin-like growth factor I receptor (IGF1R) is overexpressed in several forms of human cancer, and it has emerged as an important target for anticancer drug design. Cancer genome sequencing efforts have recently identified three somatic mutations in IGF1R: A1374V, a deletion of S1278 in the C-terminal tail region of the receptor, and M1255I in the C-terminal lobe of the kinase catalytic domain. The possible effects of these mutations on IGF1R activity and biological function have not previously been tested. Here, we tested the effects of the mutations on the in vitro biochemical activity of IGF1R and on major IGF1R signaling pathways in mammalian cells. While the mutations do not affect the intrinsic tyrosine kinase activity of the receptor, we demonstrate that the basal (unstimulated) levels of MAP kinase and Akt activation are increased in the mutants (relative to wild-type IGF1R). We hypothesize that the enhanced signaling potential of these mutants is due to