Proteolytic activity of nerve growth factor: a case of autocatalytic activation

Nerve growth factor is a highly specific protease that can convert plasminogen to plasmin and that can hydrolyze certain synthetic N-substituted arginine esters (e.g., Nalpha=p-toluenesulfonyl-L-arginine methyl ester (TAME); N.S. Orenstein et al. (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 5497). Hydrolysis of TAME is characterized by a lag phase of lower velocity which precedes development of the steady-state maximal velcity. Kinetic analyses indicate that this behavior stems from autocatalytic activation of a nerve growth factor (NGF)-zymogen by NGF. As isolated from the mouse submandibular gland at high concentration, NGF is largely enzymically inactive. Upon high dilution, the protein undergoes autocatalytic activation with concomitant generation of full enzymic activity. The biologic significance of this unusual property of NGF is not clear, but it may serve to prevent expression of enzymic activity until the protein reaches its target cell(s) or until it recognizes its physiological substrate.