Old and new concepts of insulin-like growth factor binding proteins

The insulin-like growth factors (IGFs) and their cognate receptors and binding proteins (IGFBPs) play a central role in the endocrine regulation of growth and development in mammals. The IGFs are found in serum and other biological fluids complexed to a family of six (IGFBP-1 to -6). The current dogma is that these IGFBPs bind IGFs, but not insulin, with high affinity, thereby modulating the biological actions of the IGFs. It was believed that these IGFBPs function as classical carrier proteins to transport IGFs and extend their half-lives in circulation, and regulate the mitogenic effects of IGFs at the cellular level (IGF-dependent action of IGFBPs). The last 5 years have seen several new developments in our understanding of IGFBPs: 1) IGFBPs appear to be capable of exerting biological actions in an IGF-independent manner; 2) a new concept of an IGFBP superfamily has emerged from the identification of low-affinity binders of IGFs; and 3) IGFBPs appear to bind insulin and, in some cases, modulate insulin receptor activation. This growing body of evidence indicates that IGFBPs may play more active roles in growth regulation and each IGFBP might have its own, yet to be elucidated, biological actions, beyond its ability to regulate IGF actions (IGF-independent action of IGFBPs). Undoubtedly, these findings provide more diverse and exciting directions for our future research on IGFBPs and better understanding of IGF-IGFBP physiology.