Specifying the Cellular Responses to IGF Signals: Roles of IGF-binding Proteins

Regulation of peptide growth factor/hormone activities by secreted hormone-binding proteins has emerged as a common theme in cell-cell signaling. Among the best-studied examples are members of the IGF-binding protein (IGFBP) gene family. These secreted proteins bind the IGF ligands with equal or even greater affinities than do the IGF receptors, and therefore are placed in a critical regulatory position between IGFs and their cell surface receptors. The circulating IGF/IGFBP complexes prolong the half-lives of IGFs and buffer the potential hypoglycemic effects of IGFs. Locally expressed IGFBPs provide a means of localizing IGFs in specific cells and can alter the IGF biological activity. While some members of the IGFBP gene family have been consistently shown to inhibit IGF actions by preventing them from gaining access to the IGF receptors, others potentiate IGF actions by facilitating the ligand-receptor interaction. Furthermore, recent studies indicate that some IGFBPs can regulate several cellular processes through ligand-independent mechanisms. This review will focus on the roles of IGFBPs in vascular smooth muscle cells. A conceptual model of the molecular mechanisms by which IGFBPs act to determine the specific physiological outcomes of IGF stimulation is proposed and discussed.