Editors' ChoiceReceptors

Sortilin Weighs In on the Side of Death

Science's STKE  02 Mar 2004:
Vol. 2004, Issue 222, pp. tw76-TW76
DOI: 10.1126/stke.2222004TW76

Nerve growth factor (NGF) and its precursor proNGF bind to receptors on neurons to promote cell survival, differentiation, or death (see Kaplan and Miller). Two classes of receptors that interact with NGF or proNGF are members of the Trk family and p75NTR. Trk is involved in proliferation and differentiation of neurons, and p75NTR is implicated in both cell death responses and growth and survival responses. Nykjaer et al. provide evidence that the life or death response may be dictated by the absence or presence of the receptor sortilin, which forms a complex with proNGF and p75NTR. The binding of NGF, proNGF, or a glutathione S-transferase (GST) fusion protein with the part of proNGF that is cleaved to produce mature NGF (GST-pro) to the three receptors, TrkA, p75NTR, or sortilin, was assessed by surface plasmon resonance. Only sortilin bound to GST-pro, and sortilin exhibited the highest affinity for proNGF. In transfected cells, sortilin promoted the endocytosis of proNGF in the presence or absence of the other two receptors. When sortilin and p75NTR were coexpressed, surface binding of proNGF was increased compared with that when either receptor was expressed alone. Cross-linking studies indicated that proNGF, but not NGF, formed a complex with sortilin and p75NTR, but not with sortilin and TrkA. The presence of proNGF increased the interaction between p75NTR and sortilin, and the presence of both receptors on cells, either through transfection or endogenous expression, correlated with high-affinity binding of proNGF. The biological effects of proNGF, for example stimulation of cell death, were blocked by exposure of sortilin-expressing cells to neurotensin, another sortilin ligand, or GST-pro. Lack of sortilin or p75NTR prevented cell death induced by proNGF treatment. Thus, three receptors acting combinatorially with two ligands, mature NGF or proNGF, appear to determine the biological outcome of NGF signaling.

D. R. Kaplan, F. D. Miller, A move to sort life from death. Nature 427, 798-799 (2004). [Online Journal]

A. Nykjaer, R. Lee, K. K. Teng, P. Jansen, P. Madsen, M. S. Nielsen, C. Jacobsen, M. Kliemannel, E. Schwarz, T. E. Willnow, B. L. Hempstead, C. M. Petersen, Sortilin is essential for proNGF-induced neuronal cell death. Nature 427, 843-848 (2004). [Online Journal]