Insulin like growth factor binding protein (IGFBP) proteolysis: occurrence, identification, role and regulation

Despite the numerous descriptions of circulating IGFBP-3 proteolytic activity, the identity of the enzymes involved, the mechanism of regulation and the physiological significance remains unclear. However, it is clear that such proteolysis could represent the critical controls in the IGF system acting in a number of potential ways to modulate the signals affecting cell function (Fig. 1). The IGFBPs bind IGFs with greater affinity than the cell receptors and maintain IGF concentrations in the body at levels far in excess of that required for maximal stimulation of cell receptors. The control of IGF-availability from this large latent pool could therefore be equally, if not more, important as local production in determining the extent of receptor activation. Undoubtedly, proteolytic modification of the IGFBPs reduces their affinity for the IGFs and therefore potentially increase the bioavailability of these potent anabolic agents. In addition to controlling quantitatively the amount of bioavailable IGF, IGFBP-proteolysis may be very important for the dynamic function of this signalling system. As there are no intracellular stores to enable rapid changes in tissue availability via exocytosis from cellular secretory granules, IGFBP-proteolysis may provide a means for acutely altering the IGF-signal. Identification of the enzymes involved and study of their regulation has proved difficult, as the IGFBPs are extremely sensitive to proteolysis by many common serum enzymes. The precise role played by insulin and nutritional status in regulating the circulatory IGFBP proteases is unclear, but all these factors appear to be involved. An accumulation of evidence all support a close functional link between IGFBPs and proteases, particularly serine proteases. The IGFBPs seem particularly susceptible to serine proteases; IGFBP-3 can inhibit and IGFBP-4-specific serine protease, and high affinity interactions have been observed between IGFBP-3 and plasminogen and prekallikrein, and between IGFBP-5 and PAI-I. Further evidence for a such a fundamental link comes from the fibroblasts, products a 51kDa protein highly related to the Htr-A family of serine proteases from bacteria and containing an N-terminal region with considerable structural homology to the IGFBPs. This suggests that the IGFBPs may have evolved from a common ancestral gene that encoded a cellular serine protease and only later, in multicellular organisms, acquired the function of binding and modulating the extracellular insulin-like signals. Other hormone binding proteins provide interesting analogies to such a concept. Corticosteroid- binding globulin (CBG) belongs to an ancestral gene family of serine protease inhibitors including α1-antitrypsin, protein C inhibitor and α1- antichymotrypsin. It would appear that CBG has evolved to play a major role as a corticosteroid carrier and, whilst it has lost its ability to inhibit serine proteases, it can however still act as a substrate for enzymes such as neutrophil elastase, which may have important functional consequences for targeted delivery of corticosteroids. A similar evolutionary link between IGFBPs and serine proteases has interesting implications in unravelling the complex functions of the IGFBP family. Interactions between IGFBPs and serine proteases or their inhibitors may be fundamental to their range of biological actions. The potential for IGFBP proteases or their inhibitors in diagnosis or therapy is as yet undetermined. However, regulation of IGFBP proteolysis would appear to be important in the maintenance of normal healthy tissues and disruption of the proteases may be involved in the development of several pathological conditions.