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.
Lee
R
R
Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Kermani
P
P
Teng
K K
KK
Hempstead
B L
BL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005341:Fibrinolysin / Q000378:metabolism; D045683:Furin; D006801:Humans; D020128:Inhibitory Concentration 50; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D020932:Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D013381:Subtilisins / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D013381:Subtilisins; D005341:Fibrinolysin; D045683:Furin; D020782:Matrix Metalloproteinases