Sortilin is essential for proNGF-induced neuronal cell death

Sortilin (∼95 kDa) is a member of the recently discovered family of Vps10p-domain receptors, and is expressed in a variety of tissues, notably brain, spinal cord and muscle. It acts as a receptor for neurotensin, but predominates in regions of the nervous system that neither synthesize nor respond to this neuropeptide, suggesting that sortilin has additional roles. Sortilin is expressed during embryogenesis in areas where nerve growth factor (NGF) and its precursor, proNGF, have well-characterized effects. These neurotrophins can be released by neuronal tissues, and they regulate neuronal development through cell survival and cell death signalling. NGF regulates cell survival and cell death via binding to two different receptors, TrkA and p75NTR (ref. 10). In contrast, proNGF selectively induces apoptosis through p75NTR but not TrkA. However, not all p75NTR-expressing cells respond to proNGF, suggesting that additional membrane proteins are required for the induction of cell death. Here we report that proNGF creates a signalling complex by simultaneously binding to p75NTR and sortilin. Thus sortilin acts as a co-receptor and molecular switch governing the p75NTR-mediated pro-apoptotic signal induced by proNGF.

[1]  M. Chao,et al.  Neurotrophins and their receptors: A convergence point for many signalling pathways , 2003, Nature Reviews Neuroscience.

[2]  R. Stephens,et al.  The Cytoplasmic and Transmembrane Domains of the p75 and Trk A Receptors Regulate High Affinity Binding to Nerve Growth Factor* , 2001, The Journal of Biological Chemistry.

[3]  H. Vorum,et al.  Mannose 6-Phosphate/Insulin-like Growth Factor–II Receptor Targets the Urokinase Receptor to Lysosomes via a Novel Binding Interaction , 1998, The Journal of cell biology.

[4]  P. McCrea,et al.  Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin , 2003, Oncogene.

[5]  J. Kim,et al.  ProNGF Induces p75-Mediated Death of Oligodendrocytes following Spinal Cord Injury , 2002, Neuron.

[6]  P. Madsen,et al.  Activation and Functional Characterization of the Mosaic Receptor SorLA/LR11* , 2001, The Journal of Biological Chemistry.

[7]  B. Palsson,et al.  The Escherichia coli MG1655 in silico metabolic genotype: its definition, characteristics, and capabilities. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[8]  G. Church,et al.  Analysis of optimality in natural and perturbed metabolic networks , 2002 .

[9]  J. Hopfield,et al.  From molecular to modular cell biology , 1999, Nature.

[10]  W. Hasan,et al.  Sympathetic neurons synthesize and secrete pro-nerve growth factor protein. , 2003, Journal of neurobiology.

[11]  D. Fell,et al.  A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks , 2000, Nature Biotechnology.

[12]  B. Hempstead,et al.  High affinity nerve growth factor binding displays a faster rate of association than p140trk binding. Implications for multi-subunit polypeptide receptors. , 1994, The Journal of biological chemistry.

[13]  Albert,et al.  Emergence of scaling in random networks , 1999, Science.

[14]  T. Jovin,et al.  Ligand-Induced Internalization of the p75 Neurotrophin Receptor: A Slow Route to the Signaling Endosome , 2003, The Journal of Neuroscience.

[15]  R. Albert,et al.  The large-scale organization of metabolic networks , 2000, Nature.

[16]  R. Jaenisch,et al.  Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system , 1992, Cell.

[17]  László Lovász,et al.  Hit-and-run mixes fast , 1999, Math. Program..

[18]  B. Michalski,et al.  The Precursor Pro-Nerve Growth Factor Is the Predominant Form of Nerve Growth Factor in Brain and Is Increased in Alzheimer's Disease , 2001, Molecular and Cellular Neuroscience.

[19]  B. Hempstead,et al.  Expression of functional nerve growth factor receptors after gene transfer. , 1989, Science.

[20]  B. Palsson,et al.  In silico predictions of Escherichia coli metabolic capabilities are consistent with experimental data , 2001, Nature Biotechnology.

[21]  N. W. Davis,et al.  The complete genome sequence of Escherichia coli K-12. , 1997, Science.

[22]  I. Hermans-Borgmeyer,et al.  Expression of the 100-kDa neurotensin receptor sortilin during mouse embryonal development. , 1999, Brain research. Molecular brain research.

[23]  A. Beaudet,et al.  Distribution of NTS3 receptor/sortilin mRNA and protein in the rat central nervous system , 2003, The Journal of comparative neurology.

[24]  S. Schuster,et al.  Metabolic network structure determines key aspects of functionality and regulation , 2002, Nature.

[25]  K. Goh,et al.  Universal behavior of load distribution in scale-free networks. , 2001, Physical review letters.

[26]  Marc Barthelemy,et al.  Spatial structure of the internet traffic , 2003 .

[27]  U. Sauer,et al.  Metabolic flux profiling of Escherichia coli mutants in central carbon metabolism using GC-MS. , 2003, European journal of biochemistry.

[28]  C. Pozniak,et al.  The p75 Neurotrophin Receptor Mediates Neuronal Apoptosis and Is Essential for Naturally Occurring Sympathetic Neuron Death , 1998, The Journal of cell biology.

[29]  Barbara L. Hempstead,et al.  Regulation of Cell Survival by Secreted Proneurotrophins , 2001, Science.

[30]  P. Madsen,et al.  The sortilin cytoplasmic tail conveys Golgi–endosome transport and binds the VHS domain of the GGA2 sorting protein , 2001, The EMBO journal.

[31]  U. Sauer,et al.  Metabolic Flux Ratio Analysis of Genetic and Environmental Modulations of Escherichia coli Central Carbon Metabolism , 1999, Journal of bacteriology.

[32]  D. Kaplan,et al.  High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor , 1991, Nature.

[33]  T. McCaffrey,et al.  p75(NTR) mediates neurotrophin-induced apoptosis of vascular smooth muscle cells. , 2000, The American journal of pathology.

[34]  An-Ping Zeng,et al.  The Connectivity Structure, Giant Strong Component and Centrality of Metabolic Networks , 2003, Bioinform..

[35]  Robert L. Smith,et al.  Efficient Monte Carlo Procedures for Generating Points Uniformly Distributed over Bounded Regions , 1984, Oper. Res..

[36]  P. Madsen,et al.  Characterization of sorCS1, an Alternatively Spliced Receptor with Completely Different Cytoplasmic Domains That Mediate Different Trafficking in Cells* , 2003, The Journal of Biological Chemistry.

[37]  B. Palsson,et al.  Characterizing the metabolic phenotype: A phenotype phase plane analysis , 2002, Biotechnology and bioengineering.

[38]  U. Sauer,et al.  Metabolic Flux Responses to Pyruvate Kinase Knockout in Escherichia coli , 2002, Journal of bacteriology.

[39]  F. Giancotti,et al.  Axonal regulation of Schwann cell integrin expression suggests a role for alpha 6 beta 4 in myelination , 1993, The Journal of cell biology.

[40]  E Schwarz,et al.  The pro-sequence facilitates folding of human nerve growth factor from Escherichia coli inclusion bodies. , 2001, European journal of biochemistry.

[41]  J. Fyfe,et al.  Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D3 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[42]  M. Kaghad,et al.  The 100-kDa Neurotensin Receptor Is gp95/Sortilin, A Non-G-Protein-coupled Receptor* , 1998, The Journal of Biological Chemistry.

[43]  D. Fell,et al.  The small world inside large metabolic networks , 2000, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[44]  A. Barabasi,et al.  Hierarchical Organization of Modularity in Metabolic Networks , 2002, Science.

[45]  Kazuhisa Sakai,et al.  Involvement of TLCK‐sensitive serine protease in colchicine‐induced cell death of sympathetic neurons in culture , 2001, Journal of neuroscience research.

[46]  J. W. Campbell,et al.  Experimental Determination and System Level Analysis of Essential Genes in Escherichia coli MG1655 , 2003, Journal of bacteriology.

[47]  U. Sauer,et al.  Metabolic flux response to phosphoglucose isomerase knock-out in Escherichia coli and impact of overexpression of the soluble transhydrogenase UdhA. , 2001, FEMS Microbiology Letters.

[48]  S. Moestrup,et al.  Propeptide cleavage conditions sortilin/neurotensin receptor‐3 for ligand binding , 1999, The EMBO journal.

[49]  N. Tommerup,et al.  Molecular Identification of a Novel Candidate Sorting Receptor Purified from Human Brain by Receptor-associated Protein Affinity Chromatography* , 1997, The Journal of Biological Chemistry.

[50]  T. McCaffrey,et al.  p75NTR Mediates Neurotrophin-Induced Apoptosis of Vascular Smooth Muscle Cells , 2000 .

[51]  S. Alemà,et al.  Modulation of nerve growth factor internalization by direct interaction between p75 and TrkA receptors , 1997, Journal of neuroscience research.

[52]  B. Snel,et al.  Pathway alignment: application to the comparative analysis of glycolytic enzymes. , 1999, The Biochemical journal.

[53]  E. Shooter,et al.  The Biosynthesis of Neurotrophin Heterodimers by Transfected Mammalian Cells (*) , 1995, The Journal of Biological Chemistry.

[54]  B. Palsson,et al.  Escherichia coli K-12 undergoes adaptive evolution to achieve in silico predicted optimal growth , 2002, Nature.

[55]  Petter Holme,et al.  Subnetwork hierarchies of biochemical pathways , 2002, Bioinform..