Craddock Barbara P, Miller W Todd
Department of Physiology and Biophysics, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
J Signal Transduct. 2012;2012:804801. doi: 10.1155/2012/804801. Epub 2012 Jun 14.
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.
胰岛素样生长因子I受体（IGF1R）在多种人类癌症中过度表达，已成为抗癌药物设计的重要靶点。癌症基因组测序研究最近在IGF1R中鉴定出三种体细胞突变：A1374V，受体C末端尾部区域S1278缺失，以及激酶催化结构域C末端叶中的M1255I。这些突变对IGF1R活性和生物学功能的可能影响此前尚未得到测试。在此，我们测试了这些突变对IGF1R体外生化活性以及哺乳动物细胞中主要IGF1R信号通路的影响。虽然这些突变不影响受体的内在酪氨酸激酶活性，但我们证明突变体中MAP激酶和Akt激活的基础（未刺激）水平相对于野生型IGF1R有所增加。我们推测这些突变体增强的信号传导潜力是由于IGF1R C末端与细胞底物或调节剂之间蛋白质 - 蛋白质相互作用的变化。
