The many faces of IGF-1R from cell surface to the nucleus

The IGF-1R is due to its implication in cancer an intensively studied subject of research. It is well known today that intracellular signals mediated by the IGF-1R play pivotal roles in tumorigenesis and cancer progression. However, the focus has been lying mainly on the classic canonical biochemical cascades originating from the cell surface receptor resulting in proliferation and sustained cell survival mediated by receptor activation and phosphorylation. The impact of other modifications, like ubiquitination, has just recently begun to be appreciated. In addition, the detection of nuclear IGF-1R in cancer cells implicates a novel role for the receptor in tumor biology. In paper I, we focus on IGF-1R ubiquitination and analyze its role in receptor signaling and degradation. By using wild type and different mutated IGF-1R constructs, we identified functional sites and domains necessary for receptor ubiquitination. We show that ubiquitination requires receptor tyrosine kinase activity and that the C-terminal domain of IGF-1R is necessary for ubiquitination and ERK phosphorylation as well as for proteasomal degradation of the receptor. The second paper identifies c-Cbl as novel ubiquitin ligase for IGF-1R. We present the findings that c-Cbl mediates Lys48 polyubiquitination and internalization through lipid raft dependent endocytosis upon high dose IGF-1 stimulation. In paper III, we utilize a mutant form of IGF-1R which is autophosphorylation-deficient and demonstrate that FAK phosphorylates the receptor in an a-loop independent manner. Furthermore, FAK stabilizes IGF-1R protein levels and enables downstream signaling in cells expressing the mutant form of IGF-1R through MAPK/Erk and PI3K/Akt pathway. In paper IV we aimed to reveal the impact of nuclear IGF-1R on gene transcription. We show that, apart from its classical tyrosine kinase activity, IGF-1R binds to and activates the ß-catenin/LEF-1 transcription complex in the nucleus and increases protein levels of cyclin D1 and c-Myc. Taken together, our studies provide new aspects of IGF-1R modification and identified novel interaction partners. We also present an additional molecular mechanism by which IGF-1R may promote uncontrolled cell proliferation