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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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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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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DOI: https://doi.org/10.1038/nature02319
