Regulation of cell survival by secreted proneurotrophins

Neurotrophins are growth factors that promote cell, survival, differentiati on, and cell death. They are synthesized as proforms that can be cleaved in tracellularly to release mature, secreted Ligands. Although proneurotrophin s 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 prote ase plasmin and by selective matrix metalloproteinases (MMPs). ProNGF is a high-affinity ligand for p75(NTR) with high affinity and induced p75(NTR)-d ependent apoptosis in cultured neurons with minimal activation of TrkA-medi ated differentiation or survival. The biological action of neurotrophins is thus regulated by proteolytic cleavage, with proforms preferentially activ ating p75(NTR) to mediate apoptosis and mature forms activating Trk recepto rs to promote survival.