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Sortilin is essential for proNGF-induced neuronal cell death

Nature volume 427, pages 843–848 (2004)Cite this article

Abstract

Sortilin1 (∼95 kDa) is a member of the recently discovered family of Vps10p-domain receptors2,3, and is expressed in a variety of tissues, notably brain, spinal cord and muscle. It acts as a receptor for neurotensin4,5, but predominates in regions of the nervous system that neither synthesize nor respond to this neuropeptide6, suggesting that sortilin has additional roles. Sortilin is expressed during embryogenesis7 in areas where nerve growth factor (NGF) and its precursor, proNGF, have well-characterized effects6,7. These neurotrophins can be released by neuronal tissues8,9, 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 TrkA11. 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.

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Figure 1: SPR analysis of ligand binding.
Figure 2: Binding and uptake of proNGF and NGF in 293 cells.
Figure 3: ProNGF-induced formation of heterotrimeric complexes comprising sortilin and p75NTR.
Figure 4: Sortilin is required for the pro-apoptotic action of proNGF.

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References

  1. Petersen, C. M. et al. Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. J. Biol. Chem. 272, 3599–3605 (1997)

    CAS  PubMed  Google Scholar 

  2. Hermey, G. et al. Characterization of sorCS1, an alternatively spliced receptor with completely different cytoplasmic domains that mediate different trafficking in cells. J. Biol. Chem. 278, 7390–7396 (2003)

    CAS  PubMed  Google Scholar 

  3. Jacobsen, L. et al. Activation and functional characterization of the mosaic receptor SorLA/LR11. J. Biol. Chem. 276, 22788–22796 (2001)

    CAS  PubMed  Google Scholar 

  4. Mazella, J. et al. The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J. Biol. Chem. 273, 26273–26276 (1998)

    CAS  PubMed  Google Scholar 

  5. Munck, P. C. et al. Propeptide cleavage conditions sortilin/neurotensin receptor-3 for ligand binding. EMBO J. 18, 595–604 (1999)

    Google Scholar 

  6. Sarret, P. et al. Distribution of NTS3 receptor/sortilin mRNA and protein in the rat central nervous system. J. Comp. Neurol. 461, 483–505 (2003)

    CAS  PubMed  Google Scholar 

  7. Hermans-Borgmeyer, I., Hermey, G., Nykjaer, A. & Schaller, C. Expression of the 100-kDa neurotensin receptor sortilin during mouse embryonal development. Brain Res. Mol. Brain Res. 65, 216–219 (1999)

    CAS  PubMed  Google Scholar 

  8. Beattie, M. S. et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36, 375–386 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hasan, W., Pedchenko, T., Krizsan-Agbas, D., Baum, L. & Smith, P. G. Sympathetic neurons synthesize and secrete pro-nerve growth factor protein. J. Neurobiol. 57, 38–53 (2003)

    CAS  PubMed  Google Scholar 

  10. Chao, M. V. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nature Rev. Neurosci. 4, 299–309 (2003)

    CAS  Google Scholar 

  11. Lee, R., Kermani, P., Teng, K. K. & Hempstead, B. L. Regulation of cell survival by secreted proneurotrophins. Science 294, 1945–1948 (2001)

    ADS  CAS  Google Scholar 

  12. Esposito, D. et al. The cytoplasmic and transmembrane domains of the p75 and Trk A receptors regulate high affinity binding to nerve growth factor. J. Biol. Chem. 276, 32687–32695 (2001)

    CAS  PubMed  Google Scholar 

  13. Mahadeo, D., Kaplan, L., Chao, M. V. & Hempstead, B. L. High affinity nerve growth factor binding displays a faster rate of association than p140trk binding. Implications for multi-subunit polypeptide receptors. J. Biol. Chem. 269, 6884–6891 (1994)

    CAS  PubMed  Google Scholar 

  14. Fahnestock, M., Michalski, B., Xu, B. & Coughlin, M. D. The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease. Mol. Cell. Neurosci. 18, 210–220 (2001)

    CAS  PubMed  Google Scholar 

  15. Heymach, J. V. Jr & Shooter, E. M. The biosynthesis of neurotrophin heterodimers by transfected mammalian cells. J. Biol. Chem. 270, 12297–12304 (1995)

    CAS  PubMed  Google Scholar 

  16. Nielsen, M. S. et al. The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein. EMBO J. 20, 2180–2190 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gargano, N., Levi, A. & Alema, S. Modulation of nerve growth factor internalization by direct interaction between p75 and TrkA receptors. J. Neurosci. Res. 50, 1–12 (1997)

    CAS  PubMed  Google Scholar 

  18. Bronfman, F. C., Tcherpakov, M., Jovin, T. M. & Fainzilber, M. Ligand-induced internalization of the p75 neurotrophin receptor: a slow route to the signaling endosome. J. Neurosci. 23, 3209–3220 (2003)

    CAS  PubMed  Google Scholar 

  19. Shonukan, O., Bagayogo, I., McCrea, P., Chao, M. & Hempstead, B. Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin. Oncogene 22, 3616–3623 (2003)

    CAS  PubMed  Google Scholar 

  20. Lee, K. F. et al. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69, 737–749 (1992)

    CAS  PubMed  Google Scholar 

  21. Rattenholl, A. et al. The pro-sequence facilitates folding of human nerve growth factor from Escherichia coli inclusion bodies. Eur. J. Biochem. 268, 3296–3303 (2001)

    CAS  Google Scholar 

  22. Hempstead, B. L., Schleifer, L. S. & Chao, M. V. Expression of functional nerve growth factor receptors after gene transfer. Science 243, 373–375 (1989)

    ADS  CAS  PubMed  Google Scholar 

  23. Hempstead, B. L., Martin-Zanca, D., Kaplan, D. R., Parada, L. F. & Chao, M. V. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350, 678–683 (1991)

    ADS  CAS  PubMed  Google Scholar 

  24. Nykjaer, A. et al. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc. Natl Acad. Sci. USA 98, 13895–13900 (2001)

    ADS  CAS  PubMed  Google Scholar 

  25. Einheber, S., Milner, T. A., Giancotti, F. & Salzer, J. L. Axonal regulation of Schwann cell integrin expression suggests a role for α6 β4 in myelination. J. Cell Biol. 123, 1223–1236 (1993)

    CAS  PubMed  Google Scholar 

  26. Nykjaer, A. et al. Mannose 6-phosphate/insulin-like growth factor-II receptor targets the urokinase receptor to lysosomes via a novel binding interaction. J. Cell Biol. 141, 815–828 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, S. et al. p75(NTR) mediates neurotrophin-induced apoptosis of vascular smooth muscle cells. Am. J. Pathol. 157, 1247–1258 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mitsui, C., Sakai, K., Ninomiya, T. & Koike, T. Involvement of TLCK-sensitive serine protease in colchicine-induced cell death of sympathetic neurons in culture. J. Neurosci. Res. 66, 601–611 (2001)

    CAS  PubMed  Google Scholar 

  29. Bamji, S. X. et al. The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. J. Cell Biol. 140, 911–923 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M. V. Chao and G. R. Lewin for valuable discussions. J. Salzer, R. Kraemer and P. Fischer are acknowledged for reagents and advice, and S. Tevar for assistance in p75NTR mice genotyping. This work was supported by the Novo Nordisk Foundation, The Danish Medical Research Council, The Carlsberg Foundation (A.N. and C.M.P.) and the NIH (B.L.H. and R.L.).

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Authors and Affiliations

  1. Department of Medical Biochemistry, Ole Worms Allé 170, Aarhus University, Gustav Wieds vej 10, DK-8000, Aarhus C, Denmark

    Anders Nykjaer, Pernille Jansen, Peder Madsen, Morten S. Nielsen, Christian Jacobsen & Claus M. Petersen

  2. ReceptIcon Aps, Gustav Wieds vej 10, DK-8000, Aarhus C, Denmark

    Anders Nykjaer & Thomas E. Willnow

  3. Weill Medical College of Cornell University, New York, 10021, New York, USA

    Ramee Lee, Kenneth K. Teng & Barbara L. Hempstead

  4. Max-Delbrück-Center for Molecular Medicine, 13125, Berlin, Germany

    Pernille Jansen & Thomas E. Willnow

  5. Institute for Biotechnology, Martin-Luther-Universität, Halle-Wittenberg, 06120, Halle, Germany

    Marco Kliemannel & Elisabeth Schwarz

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Correspondence to Anders Nykjaer.

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Nykjaer, A., Lee, R., Teng, K. et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature 427, 843–848 (2004). https://doi.org/10.1038/nature02319

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