Nuclear localization and actions of the insulin-like growth factor 1 (IGF-1) system components: Transcriptional regulation and DNA damage response

Abstract Insulin-like growth factor (IGF) system stimulates growth, proliferation, and regulates differentiation of cells in a tissue-specific manner. It is composed of two insulin-like growth factors (IGF-1 and IGF-2), six insulin-like growth factor-binding proteins (IGFBPs), and two insulin-like growth factor receptors (IGF-1R and IGF-2R). IGF actions take place mostly through the activation of the plasma membrane-bound IGF-Rs by the circulating ligands (IGFs) released from the IGFBPs that stabilize their levels in the serum. This review focuses on the IGF-1 part of the system. The IGF-1 gene, which is expressed mainly in the liver as well as in other tissues, comprises six alternatively spliced exons that code for three protein isoforms (pro-IGF-1A, pro-IGF-1B, and pro-IGF-1C), which are processed to mature IGF-1 and E-peptides. The IGF-1R undergoes autophosphorylation, resulting in a signaling cascade involving numerous cytoplasmic proteins such as AKT and MAPKs, which regulate the expression of target genes. However, a more complex picture of the axis has recently emerged with all its components being translocated to the nuclear compartment. IGF-1R takes part in the regulation of gene expression by forming transcription complexes, modifying the activity of chromatin remodeling proteins, and participating in DNA damage tolerance mechanisms. Four IGFBPs contain a nuclear localization signal (NLS), which targets them to the nucleus, where they regulate gene expression (IGFBP-2, IGFBP-3, IGFBP-5, IGFBP-6) and DNA damage repair (IGFBP-3 and IGFBP-6). Last but not least, the IGF-1B isoform has been reported to be localized in the nuclear compartment. However, no specific molecular actions have been assigned to the nuclear pro-IGF-1B or its derivative EB peptide. Therefore, further studies are needed to shed light on their nuclear activity. These recently uncovered nuclear actions of different components of the IGF-1 axis are relevant in cancer cell biology and are discussed in this review.