Insulin-like growth factor-binding proteins: functional diversity or redundancy?

The insulin-like growth factor-binding proteins (IGFBPs) represent a family of conserved proteins that share the ability to bind the insulin-like growth factors, IGF-I and IGF-II, with affinities comparable to their respective receptors. Unlike the transmembrane IGF receptors, the IGFBPs are secreted proteins. Although many of the IGFBPs are able to interact with cell surface membranes, there is no convincing evidence as yet that these binding sites function as signal transducers. The IGFBPs are present in the serum, virtually all biological fluids, tissue extracts and conditioned medium from a variety of cell lines. They appear to be present and conserved in lower species, suggesting a functionally important role throughout evolution. Although the presence of IGFBPs was first suspected in the early days of somatomedin research in the 1960s, the elucidation of their nature and complexity had to await the development of molecular techniques. Six high-affinity members of this family of proteins have been identified and the cognate cDNAs for these binding proteins have been cloned from a variety of species. An additional four potential members of the IGFBP family have been identified through computer analysis of GenBank sequence data, on the basis of the presence of the IGFBP motif, GCGCCXXC (Rosenfeld 1998). These have considerably reduced binding affinity for the IGFs and, at the recent Fourth International IGF Symposium, the consensus opinion was that these proteins should be categorized as IGFBP-related proteins (IGFBPRPs-1 to -4). In the past decade, there has been a multitude of publications dealing with the IGFBPs. Whereas initial research focused on their role as modulators of IGF action, it is now appreciated that at least some of IGFBPs have additional IGF-independent functions. It is also important to remember that the vast majority of data concerning the biological functions of the IGFBPs have been obtained from in vitro cell culture conditions, in which concentrations of the IGFs and their binding proteins used may not match those encountered in vivo. Supraphysiological concentrations and nonphysiological conditions may well account for the confusing and often contradictory results obtained in vitro: for example, both IGFBPs-1 and -3 have been shown to have stimulatory and inhibitory effects on IGF-I-induced actions in cell culture. In vivo studies of IGFBP action have been limited until recently by the lack of large quantities of purified IGFBP. With development of transgenic and knockout mouse models, some insights into the physiological role of the IGFBPs are now starting to emerge. However, the limited phenotype of the IGFBP-3-overexpressing mice (Murphy et al. 1995) and the IGFBP-2 and IGFBP-4 knockout mice (Wood et al. 1993, Pintar et al. 1997) have led to the need to reconsider the potential physiological roles of these binding proteins. In the absence of a clear understanding of the physiological role of the individual IGFBPs, some investigators have speculated that there may be considerable functional redundancy in the IGFBP family. Here, I will review some of the similarities and differences between the IGFBPs and some recent insights into the biological functions of these proteins.