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Spinnler, Katrin; Fröhlich, Thomas; Arnold, Georg J.; Kunz, Lars ORCID: 0000-0003-3141-0005; Mayerhofer, Artur (2011): Human Tryptase Cleaves Pro-Nerve Growth Factor (Pro-NGF): Hints of local, mast cell-dependent regulation of NGF/PRO-NGF action. In: Journal of Biological Chemistry, Vol. 286, No. 36: pp. 31707-31713
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Several factors regulate nerve growth factor (NGF), which is formed from pro-NGF by intracellular and extracellular enzymatic cleavage. The close proximity between mast cells expressing the protease tryptase and NGF-producing smooth muscle-like peritubular cells in the testes of infertile patients led us to examine whether tryptase is among those factors. Human peritubular cells express functional tryptase receptors (PAR-2). Recombinant enzymatically active beta-tryptase increased NGF levels in the culture medium of primary human peritubular cells, but the peptide agonist for PAR-2 (SLIGKV) did not. Neither tryptase nor the peptide increased NGF mRNA levels. To test whether the increase in NGF is due to enzymatic activity of tryptase acting on pro-NGF, supernatants of peritubular cells and synthetic pro-NGF were treated with tryptase. Results of Western blot studies indicate enzymatic cleavage of pro-NGF by active tryptase. Heat-inactivated tryptase or SLIGKV was not effective. Mass spectrometry analysis of in vitro cleavage products from recombinant tryptase and synthetic pro-NGF revealed multiple cleavage sites within the pro-NGF sequence. The results also indicate the generation of mature NGF and smaller NGF fragments as a result of tryptase action. Thus, tryptase-secreting mast cells in the vicinity of pro-NGF/NGF-secreting cells in any human tissue are likely able to alter the ratios of pro-NGF/NGF. As NGF and pro-NGF have different affinities for their receptors, this indicates a novel way by which mast cells, via tryptase, can modify the microenvironment in human tissues with regard to neurotrophin actions.