NGF and ProNGF: Regulation of neuronal and neoplastic responses through receptor signaling

Abstract

Nerve growth factor (NGF) and its precursor (proNGF) are primarily considered as regulators of neuronal function that induce their responses via the tyrosine kinase receptor TrkA and the pan-neurotrophin receptor p75NTR. It has been generally held that NGF exerts its effects primarily through TrkA, inducing a cascade of tyrosine kinase-initiated responses, while proNGF binds more strongly to p75NTR. When this latter entity interacts with a third receptor, sortilin, apoptotic responses are induced in contrast to the survival/differentiation associated with the other two. Recent studies have outlined portions of the downstream phosphoproteome of TrkA in the neuronal PC12 cells and have clarified the contribution of individual docking sites in the TrkA endodomain. The patterns observed showed a similarity with the profile induced by the epidermal growth factor receptor, which is extensively associated with oncogenesis. Indeed, as with other neurotrophic factors, the distribution of TrkA and p75NTR is not limited to neuronal tissue, thus providing an array of targets outside the nervous systems. One such source is breast cancer cells, in which NGF and proNGF stimulate breast cancer cell survival/growth and enhance cell invasion, respectively. This latter activity is exerted via TrkA (as opposed to p75NTR) in conjunction with sortilin. Another tissue overexpressing proNGF is prostate cancer and here the ability of cancer cells to induce neuritogenesis has been implicated in cancer progression. These studies show that the non-neuronal functions of proNGF/NGF are likely integrated with their neuronal activities and point to the clinical utility of these growth factors and their receptors as biomarkers and therapeutic targets for metastasis and cancer pain.

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

“…NGF is post-translationally cleaved from proNGF to mature NGF (mNGF), and these two isoforms exert different biological effects (43). Therefore, we used Western blot to determine the relative predominance of proNGF or mNGF in disc cell-conditioned medium after 48 h of treatment.…”

ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels

“…Furthermore, cancer cells respond directly to NGF and proNGF, to exacerbate cancer-related phenotypes [44]. For example, proNGF can stimulate the invasion of melanoma and breast cancer cells through the activation of p75NTR/sortilin and TrkA/sortilin, respectively [44,45,46]. In fact, an increased expression of TrkA, as observed in breast cancer, is associated with enhanced growth and metastasis [47].…”

Mechanisms and regulation of neurotrophin synthesis and secretion

“…The PCs are a family of serine endoproteases, which are members of the subtilisin super family that activate protein precursors. They include, furin, PC1/PC3, PC2, PC4, PACE5, PC5/PC6, PC7/LPC, PC8, and the mammalian pyrolysin-like enzyme known as SKI-1/S1P 11,12. The PCs cleave precursor proteins behind a pair of basic residues Arginine Arginine or Lysine Arginine.…”