Cellular Actions of the Insulin-Like Growth Factor Binding Proteins

In addition to their roles in IGF transport, the six IGF-binding proteins (IGFBPs) regulate cell activity in various ways. By sequestering IGFs away from the type I IGF receptor, they may inhibit mitogenesis, differentiation, survival, and other IGF-stimulated events. IGFBP proteolysis can reverse this inhibition or generate IGFBP fragments with novel bioactivity. Alternatively, IGFBP interaction with cell or matrix components may concentrate IGFs near their receptor, enhancing IGF activity. IGF receptor-independent IGFBP actions are also increasingly recognized. IGFBP-1 interacts with 5 1 integrin, influencing cell adhesion and migration. IGFBP-2, -3, -5, and -6 have heparin-binding domains and can bind glycosaminoglycans. IGFBP-3 and -5 have carboxyl-terminal basic motifs incorporating heparin-binding and additional basic residues that interact with the cell surface and matrix, the nuclear transporter importin-, and other proteins. Serine/ threonine kinase receptors are proposed for IGFBP-3 and -5, but their signaling functions are poorly understood. Other cell surface IGFBP-interacting proteins are uncharacterized as functional receptors. However, IGFBP-3 binds and modulates the retinoid X receptor-, interacts with TGF signaling through Smad proteins, and influences other signaling pathways. These interactions can modulate cell cycle and apoptosis. Because IGFBPs regulate cell functions by diverse mechanisms, manipulation of IGFBP-regulated pathways is speculated to offer therapeutic opportunities in cancer and other diseases. (Endocrine Reviews 23: 824 -854, 2002) I. Introductory Overview A. IGFBP structure B. Relationship between serum and tissue IGFBPs II. Modulation of IGF Activity by IGFBPs and Their Proteases A. IGFBP-4, -5, and -6 B. IGFBP-1, -2, and -3 III. IGF and IGFRI-Independent Effects of IGFBPs IV. Adhesion and Migration V. Cell-Binding Sites and Putative Receptors A. Glycosaminoglycan-binding domains on IGFBPs B. The role of posttranslational modifications in cell surface association C. Other putative IGFBP receptors VI. Interactions of IGFBP-3 with Known Signaling Pathways A. IGFBP-3 and TGF signaling B. IGFBP-3, retinoids, and nuclear signaling C.