7S nerve growth factor is an insulin-like growth factor-binding protein protease.
Insulin-like growth factor (IGF)-binding protein (IGFBP) proteases modulate IGF action by cleaving IGFBPs into fragments with lower affinity to IGFs, thereby increasing the levels of free IGFs. We have previously documented that prostate-specific antigen (PSA), a serine protease of the kallikrein family, is an IGFBP-3 protease. In this study, we characterized the potential IGFBP proteolytic activity of nerve growth factor (NGF gamma-subunit), which shares high sequence homology with PSA. [125I]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, had a lower affinity to IGFs than intact IGFBP-3. Unlike PSA, which cleaves primarily IGFBP-3 and -5, NGF also displayed potent proteolytic activity against IGFBP-4 and -6. These data suggest that NGF may be involved 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 may have important implications on cell growth, development, and repair in the brain and other tissues.
Rajah
R
R
Endocrine Division, Department of Pediatrics, University of Pennsylvania, Phildelphia, USA.
Bhala
A
A
Nunn
S E
SE
Peehl
D M
DM
Cohen
P
P
D015153:Blotting, Western; D010450:Endopeptidases / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D009414:Nerve Growth Factors / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification; D017430:Prostate-Specific Antigen / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
C488871:7S nerve growth factor protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D010450:Endopeptidases; D007610:Kallikreins; D017430:Prostate-Specific Antigen; C080473:insulin-like growth factor binding protein-3 protease