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Science 30 November 2001:
Vol. 294. no. 5548, pp. 1945 - 1948
DOI: 10.1126/science.1065057
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Reports

Regulation of Cell Survival by Secreted Proneurotrophins

Ramee Lee, Pouneh Kermani, Kenneth K. Teng, Barbara L. Hempstead*

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 p75NTR 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.

Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
*   To whom correspondence should be addressed: E-mail: blhempst{at}med.cornell.edu

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Ligand-Induced Internalization of the p75 Neurotrophin Receptor: A Slow Route to the Signaling Endosome.
F. C. Bronfman, M. Tcherpakov, T. M. Jovin, and M. Fainzilber (2003)
J. Neurosci. 23, 3209-3220
   Abstract »    Full Text »    PDF »
Airway Neural Plasticity: The Nerves They Are A-Changin'.
D. B. Jacoby (2003)
Am. J. Respir. Cell Mol. Biol. 28, 138-141
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Making sense of latent TGF{beta} activation.
J. P. Annes, J. S. Munger, and D. B Rifkin (2003)
J. Cell Sci. 116, 217-224
   Abstract »    Full Text »    PDF »
The Neurotrophin Receptor p75NTR as a Positive Modulator of Myelination.
J. M. Cosgaya, J. R. Chan, and E. M. Shooter (2002)
Science 298, 1245-1248
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Cyclic AMP Induces Transactivation of the Receptors for Epidermal Growth Factor and Nerve Growth Factor, Thereby Modulating Activation of MAP Kinase, Akt, and Neurite Outgrowth in PC12 Cells.
A. Piiper, I. Dikic, M. P. Lutz, J. Leser, B. Kronenberger, R. Elez, H. Cramer, W. Muller-Esterl, and S. Zeuzem (2002)
J. Biol. Chem. 277, 43623-43630
   Abstract »    Full Text »    PDF »
The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro.
M. Guipponi, G. Vuagniaux, M. Wattenhofer, K. Shibuya, M. Vazquez, L. Dougherty, N. Scamuffa, E. Guida, M. Okui, C. Rossier, et al. (2002)
Hum. Mol. Genet. 11, 2829-2836
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Rabies Virus Glycoprotein (RVG) Is a Trimeric Ligand for the N-terminal Cysteine-rich Domain of the Mammalian p75 Neurotrophin Receptor.
C. Langevin, H. Jaaro, S. Bressanelli, M. Fainzilber, and C. Tuffereau (2002)
J. Biol. Chem. 277, 37655-37662
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Reduced Apoptosis and Increased Lesion Development in the Flow-Restricted Carotid Artery of p75NTR-Null Mutant Mice.
R. Kraemer (2002)
Circ. Res. 91, 494-500
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Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice.
S. Capsoni, S. Giannotta, and A. Cattaneo (2002)
PNAS 99, 12432-12437
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TrkA as a Life and Death Receptor: Receptor Dose as a Mediator of Function.
C. Yan, Y. Liang, K. D. Nylander, and N. F. Schor (2002)
Cancer Res. 62, 4867-4875
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Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation.
M. R. Saban, N.-B. Nguyen, T. G. Hammond, and R. Saban (2002)
Am. J. Pathol. 160, 2095-2110
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Failure of Brain-Derived Neurotrophic Factor-Dependent Neuron Survival in Mouse Trisomy 16.
S. G. Dorsey, L. L. Bambrick, R. J. Balice-Gordon, and B. K. Krueger (2002)
J. Neurosci. 22, 2571-2578
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Nerve Growth Factor-induced p75-mediated Death of Cultured Hippocampal Neurons Is Age-dependent and Transduced through Ceramide Generated by Neutral Sphingomyelinase.
A. B. Brann, M. Tcherpakov, I. M. Williams, A. H. Futerman, and M. Fainzilber (2002)
J. Biol. Chem. 277, 9812-9818
   Abstract »    Full Text »    PDF »


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