Sortilin is essential for proNGF-induced neuronal cell death

Abstract

Sortilin¹ ( ∼ 95 kDa) is a member of the recently discovered family of Vps10p-domain receptors^2,3, and is expressed in a variety of tissues, notably brain, spinal cord and muscle. It acts as a receptor for neurotensin^4,5, 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 effects^6,7. These neurotrophins can be released by neuronal tissues^8,9, 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 p75^NTR (ref. 10). In contrast, proNGF selectively induces apoptosis through p75^NTR but not TrkA¹¹. However, not all p75^NTR-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 p75^NTR and sortilin. Thus sortilin acts as a co-receptor and molecular switch governing the p75^NTR-mediated pro-apoptotic signal induced by proNGF.