The insulin-like growth factor binding protein superfamily: New perspectives

The insulin-like growth factor (IGF) binding proteins (IGFBPs) were initial ly identified as carrier proteins for IGF-I and IGF-II in a variety of biol ogic fluids. Their presumed function was to protect IGF peptides from degra dation and clearance, increase the half-life of the IGFs, and deliver them to appropriate tissue receptors. The concept of IGFBPs as simple carrier pr oteins has been complicated, however, by a number of observations: 1) the s ix IGFBPs vary in their tissue expression and their regulation by other hor mones and growth factors; 2) the IGFBPs are subjected to proteolytic degrad ation, thereby altering their affinities for the IGFs; 3) IGFBP-3 and IGFBP -5, in addition to binding IGFs, also can associate with an acid-labile sub unit, thereby increasing further the half-life of the IGFs; 4) in addition to modifying the access of IGF peptides to IGF and insulin receptors, sever al of the IGFBPs may be capable of increasing IGF action; 5) some of the IG FBPs may be capable of IGF-independent regulation of cell growth; 6) some o f the IGFBPs are associated with cell membranes or possibly with membrane r eceptors; and 7) some of the IGFBPs have nuclear recognition sites and may be found within the nucleus. Additionally, a number of cDNAs identified rec ently have been found to encode proteins that bind IGFs, but with substanti ally lower affinities than is the case with IGFBPs. The N-terminal regions of the predicted proteins are structurally homologous to the classic IGFBPs , with conservation of the cysteine-rich region. These observations suggest that these low-affinity binders are members of an IGFBP superfamily, capab le of regulating cell growth by both IGF-dependent and IGF-independent mech anisms.