Regulation of Cell Survival by Secreted Proneurotrophins

TLDR

Neurotrophins are growth factors that regulate cell survival, differentiation, and death, produced as proforms that can be cleaved to release mature ligands that preferentially activate Trk receptors for survival or p75 NTR for apoptosis. We demonstrate that proneurotrophins NGF and BDNF are secreted and cleaved extracellularly by plasmin and MMPs, and that proNGF binds p75 NTR with high affinity to trigger apoptosis while minimally activating TrkA-mediated survival pathways.

Abstract

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 p75 NTR -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 p75 NTR to mediate apoptosis and mature forms activating Trk receptors to promote survival.