Sortilin is essential for proNGF-induced neuronal cell death

Nature. 2004 Feb 26;427(6977):843-8. doi: 10.1038/nature02319.


Sortilin (approximately 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Apoptosis / drug effects*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line
  • Cell Membrane / metabolism
  • Electron Spin Resonance Spectroscopy
  • Humans
  • Ligands
  • Macromolecular Substances
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Weight
  • Nerve Growth Factor / chemistry
  • Nerve Growth Factor / metabolism
  • Nerve Growth Factor / pharmacology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Protein Binding / drug effects
  • Protein Precursors / chemistry
  • Protein Precursors / metabolism
  • Protein Precursors / pharmacology*
  • Protein Structure, Tertiary
  • Rats
  • Receptor, Nerve Growth Factor
  • Receptor, trkA*
  • Receptors, Nerve Growth Factor / metabolism


  • Adaptor Proteins, Vesicular Transport
  • Carrier Proteins
  • Ligands
  • Macromolecular Substances
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Protein Precursors
  • Receptor, Nerve Growth Factor
  • Receptors, Nerve Growth Factor
  • pro-nerve growth factor, human
  • pro-nerve growth factor, mouse
  • Nerve Growth Factor
  • Receptor, trkA
  • sortilin