Sortilin is essential for proNGF-induced neuronal cell death

Sortilin(1) (similar to95 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 neuropeptide(6), suggesting that sortilin has additional roles. Sortilin is expressed during embryogenesis(7) 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 TrkA(11). 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.