7S NERVE GROWTH-FACTOR IS AN INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN PROTEASE

Insulin-like growth factor (IGF)-binding protein (IGFBP) proteases mod ulate IGF action by cleaving IGFBPs into fragments with lower affinity to IGFs, thereby increasing the levels of free IGFs. We have previous ly documented that prostate-specific antigen (PSA), a serine protease of the kallikrein family, is an IGFBP-3 protease. In this study, we ch aracterized the potential IGFBP proteolytic activity of nerve growth f actor (NGF gamma-subunit), which shares high sequence homology with PS A. [I-125]IGFBP-3 was cleaved by NGF (but not other kallikreins) at a 3-fold lower concentration than that of PSA, thus proving NGF to be a more potent IGFBP protease than PSA. NGF-generated, lower mol wt IGFBP -3 fragments, detected by immunoblotting and cross-linking to IGFs, ha d a lower affinity to IGFs than intact IGFBP-3. Unlike PSA, which clea ves primarily IGFBP-3 and -5, NGF also displayed potent proteolytic ac tivity against IGFBP-4 and -6. These data suggest that NGF may be invo lved in the growth of cells by more than one mechanism. In addition to binding to its receptors, NGF is capable of cleaving IGFBPs and, thus , enhancing IGF action. This synergistic action between NGF and IGF ma y have important implications on cell growth, development, and repair in the brain and other tissues.