%0 Journal Article
%T Effects of Somatic Mutations in the C-Terminus of Insulin-Like Growth Factor 1 Receptor on Activity and Signaling
%A Barbara P. Craddock
%A W. Todd Miller
%J Journal of Signal Transduction
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/804801
%X 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 changes in protein-protein interactions between the IGF1R C-terminus and cellular substrates or modulators. 1. Introduction The human genome encodes approximately 90 tyrosine protein kinases [1]. A common characteristic of these enzymes is that they are normally tightly regulated in unstimulated cells. Stimulation (e.g., by binding of a growth factor to the extracellular domain of a receptor tyrosine kinase) leads to a rapid, transient increase in tyrosine kinase activity. Constitutive activation of tyrosine kinases, however, is often observed in cancer cells. Genes that are causally implicated in human cancer frequently encode protein kinase catalytic domains [2]. Most oncogenic tyrosine kinases contain activating mutations and are dominant at the cellular level [2, 3]. The human insulin-like growth factor 1 receptor (IGF1R) is a heterotetramer containing two extracellular alpha subunits and two transmembrane beta subunits [4]. Binding of the ligand (IGF1) to the alpha subunits triggers a conformational change that leads to autophosphorylation of the intracellular kinase domains in the beta subunits [5]. Autophosphorylation greatly enhances the activity of the IGF1R catalytic domain [6]. The signal is propagated through the PI 3¡ä-kinase and MAP kinase pathways to promote proliferation and cell survival. In the unstimulated state, the basal activity of the IGF1R receptor is suppressed by autoinhibitory interactions between the activation loop and other residues in the kinase domain [6¨C8] and between the kinase domain and the juxtamembrane region [9]. Deregulated IGF1R kinase activity has
%U http://www.hindawi.com/journals/jst/2012/804801/