Regulation of cell survival by secreted proneurotrophins.
Neurotrophins are growth factors that promote cell survival, differentiation, and cell death. They are synthesized as proforms that can be cleaved intracellularly to release mature, secreted ligands. Although proneurotrophins have been considered inactive precursors, we show here that the proforms of nerve growth factor (NGF) and the proforms of brain ... derived neurotrophic factor (BDNF) are secreted and cleaved extracellularly by the serine protease plasmin and by selective matrix metalloproteinases (MMPs). ProNGF is a high-affinity ligand for p75(NTR) with high affinity and induced p75NTR-dependent apoptosis in cultured neurons with minimal activation of TrkA-mediated differentiation or survival. The biological action of neurotrophins is thus regulated by proteolytic cleavage, with proforms preferentially activating p75NTR to mediate apoptosis and mature forms activating Trk receptors to promote survival.
Mesh Terms:
Animals, Apoptosis, Brain-Derived Neurotrophic Factor, Cell Death, Cell Differentiation, Cell Line, Cell Survival, Fibrinolysin, Furin, Humans, Inhibitory Concentration 50, Matrix Metalloproteinases, Mice, Nerve Growth Factor, Nerve Growth Factors, Neurons, Phosphorylation, Protein Precursors, Protein Processing, Post-Translational, Rats, Receptor, Nerve Growth Factor, Receptor, trkA, Receptors, Nerve Growth Factor, Subtilisins
Animals, Apoptosis, Brain-Derived Neurotrophic Factor, Cell Death, Cell Differentiation, Cell Line, Cell Survival, Fibrinolysin, Furin, Humans, Inhibitory Concentration 50, Matrix Metalloproteinases, Mice, Nerve Growth Factor, Nerve Growth Factors, Neurons, Phosphorylation, Protein Precursors, Protein Processing, Post-Translational, Rats, Receptor, Nerve Growth Factor, Receptor, trkA, Receptors, Nerve Growth Factor, Subtilisins
Science
Date: Nov. 30, 2001
PubMed ID: 11729324
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