Structure and Biosynthesis of Nerve Growth Factor

Most of our knowledge about NGF comes from extensive study of the mouse submaxillary gland protein. NGF from this source is isolated as a high molecular weight complex consisting of beta-NGF and two subunits, alpha and gamma, belonging to the kallikrein family of serine proteases. There are few other tissues where NGF is found in sufficient quantities for protein purification and study, although new molecular biological techniques have accelerated the study of NGFs from a variety of species and tissues. Mouse submaxillary gland NGF is synthesized as a large precursor that is cleaved at both N- and C-terminals to produce mature NGF. This biologically active molecule can be further cleaved by submaxillary gland proteases. The roles of the alpha and gamma subunits in the processing of the beta-NGF precursor, the modulation of the biological activity of beta-NGF, and the protection of mature beta-NGF from degradation have been well studied in the mouse. However, the apparent lack of alpha and gamma subunits in most other tissues and species and the existence of a large family of murine kallikreins, many of which are expressed in the submaxillary gland, challenge the relevance of murine high molecular weight NGF as a proper model for NGF biosynthesis and regulation. It is important therefore to identify and characterize other NGF complexes and to study their subunit interactions, biosynthesis, processing, and regulation. This review points out a number of other species and tissues in which the study of NGF has just begun. At this time, there exist many more questions than answers regarding the presence and the functions of NGF processing and regulatory proteins. By studying NGF in other species and tissues and comparing the processing and regulation of NGF from several sources, we will discover the unifying concepts governing the expression of NGF biological activity.