DUAN, Cunming: EXTRACELLULAR AND NUCLEAR ACTIONS OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS

Regulation of peptide growth factor/hormone activities by secreted hormone binding proteins has emerged as a common theme in cell-cell communication. Among the best studied hormone binding proteins are members of the insulin-like growth factor binding protein (IGFBP) gene family. To date, six distinct high-affinity IGFBPs have been identified and cloned in mammalian and non-mammalian organisms. Each of these IGFBPs represents an individual gene product, and is regulated differentially. IGFBPs can act as carrier proteins in the bloodstream. The circulating IGF/IGFBP complexes prolong the half-lives of IGFs and buffer the acute hypoglycemic effects of IGFs. More importantly, since the soluble IGFBPs bind to IGFs with equal or even higher affinity than do the IGF receptors, locally expressed IGFBPs provide a means of localizing IGFs in specific cells and may alter the IGF biological activity by modulating their interaction with the IGF receptors. While some members have been consistently shown to inhibit IGF actions by preventing them from gaining access to the cell surface receptors, others can potentiate IGF actions by promoting the ligand receptor interaction. In addition to these extracellular effects of IGFBPs, recent studies from ours as well as other laboratories have shown that some IGFBPs (e.g., IGFBP-5) regulate several cellular processes through a ligand-independent mechanism that may involves their internalization and nuclear translocation. This talk will focus on the IGF-independent action of IGFBP-5, the identification of the cellular receptor and other proteins that interact with IGFBP-5. The uptake, internalization, nuclear translocation of IGFBP-5, as well as the functional importance of the nuclear IGFBP-5 will be discussed.