COHEN, P: Intracellular and Nuclear Interactions of IGFBPs

Multiple IGF-independent actions of IGFBPs have been identified in recent years. These include growth-inhibition, apoptosis, and regulation of gene expression. IGFBPs interact directly with multiple extracellular molecules with known growth regulatory functions ranging from heparin to transferrin. It is yet entirely unknown how some IGFBPs enter cells, yet several IGFBPs, including IGFBP-2, -3, and �5 have been detected intra-cellularly. Once inside the cell, IGFBPs appear to be able to enter the nucleus compatible with the presence of a nuclear localization sequence (NLS) which allows IGFBP-3 and �5 to bind beta-importin that serves as a nuclear shuttle. Recently, the human papillomavirus oncoprotein E7 was identified to bind IGFBP-3 intra-cellularly and to facilitate its proteosomal degradation, which leads to the loss of its apoptotic functions and its nuclear localization. The roles of nuclear IGFBPs appear to include transcriptional regulation of cell cycle and apoptosis-related genes. The main nuclear receptor for IGFBP-3 appears to be the retinoid receptor-X (RXR). Yeast-two hybrid, co-immunoprecipitation, GST-pull down, ligand blots, and confocal microscopy confirm specific high affinity binding of IGFBP-3 to RXR in the nucleus. IGFBP-3 enhances RXR-mediated signaling, but inhibits the signalling of the RXR partners RAR and PPAR. Furthermore, RXR knockout cells lose their response to IGFBP-3. The roles of other IGFBPs in the nucleus is under investigation. Together these lines of research lead to a clearer picture of IGFBPs as nuclear molecules, which probably serve as co-activators and co-repressors of traditional and/or orphan nuclear receptors. The significance of these IGFBP functions in diseases such as cancer and diabetes, where nuclear receptors play a key role, is being evaluated.