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.

Sortilin belongs to a growing family of multiligand type-1 receptors with homology to the yeast receptor Vps10p. Based on structural features and sortilin's intracellular predominance, we have proposed it to be a sorting receptor for ligands in the synthetic pathway as well as on the cell membrane. To test this hypothesis we examine here the cellular traf®cking of chimeric receptors containing constructs of the sortilin tail. We report that sorting signals conforming to YXXF and dileucine motifs mediate rapid endocytosis of sortilin chimeras, which subsequently travel to the trans-Golgi network, showing little or no recycling. Furthermore, we found that cation-independent mannose 6-phosphate receptor (MPR300)±sortilin chimeras, expressed in mannose 6-phosphate receptor knockout cells, were almost as ef®cient as MPR300 itself for transport of newly synthesized b-hexosaminidase and b-glucuronidase to lysosomes, and established that the sortilin tail contains potent signals for Golgi±endosome sorting. Finally, we provide evidence suggesting that sortilin is the ®rst example of a mammalian receptor targeted by the recently described GGA family of cytosolic sorting proteins, which condition the Vps10p-mediated sorting of yeast carboxypeptidase Y.

Receptor-associated protein (RAP) is an endoplasmic reticulum/Golgi protein involved in the processing of receptors of the low density lipoprotein receptor family. A ϳ95-kDa membrane glycoprotein, designated gp95/ sortilin, was purified from human brain extracts by RAP affinity chromatography and cloned in a human cDNA library. The gene maps to chromosome 1p and encodes an 833-amino acid type I receptor containing an N-terminal furin cleavage site immediately preceding the N terminus determined in the purified protein. Gp95/sortilin is expressed in several tissues including brain, spinal cord, and testis. Gp95/sortilin is not related to the low density lipoprotein receptor family but shows intriguing homologies to established sorting receptors: a 140-amino acid lumenal segment of sortilin representing a hitherto unrecognized type of extracellular module shows extensive homology to corresponding segments in each of the two lumenal domains of yeast Vps10p, and the extreme C terminus of the cytoplasmic tail of sortilin contains the casein kinase phosphorylation consensus site and an adjacent dileucine sorting motif that mediate assembly protein-1 binding and lysosomal sorting of the mannose-6-phosphate receptors. Expression of a chimeric receptor containing the cytoplasmic tail of gp95/ sortilin demonstrates evidence that the tail conveys colocalization with the cation-independent mannose-6-phosphate receptor in endosomes and the Golgi compartment.Sorting of newly synthesized lysosomal enzymes from the Golgi compartment to late endosomes in eukaryotic cells is a sophisticated transport process involving specific sorting receptors in the trans-Golgi network. In mammals, the 46-and 275-kDa mannose-6-phosphate (M6P) 1 receptors are the known sorting receptors that bind to phosphorylated mannose residues in lysosomal hydrolases (1). In yeast, a M6P-independent sorting pathway has been demonstrated by identification of the vacuolar protein-sorting 10 protein (Vps10p) (2) and a highly homologous protein encoded by the yeast VTH2 gene (3). Both are capable of targeting yeast carboxypeptidase Y to lysosomes (2, 3). Mammalian counterparts to these sorting receptors have so far not been identified. However, studies of I-cell disease patients suggest that mammals may sort lysosomal enzymes by alternative mechanisms (4 -9). The 40-kDa endoplasmic reticulum/Golgi receptor-associated protein (RAP) assists folding and processing of the cysteine-rich low density lipoprotein (LDL) receptor class A repeats in receptors of the LDL receptor family (10 -13). In addition to the high affinity binding to the LDL receptor family proteins and the newly identified LDL receptor type A repeat containing receptor sorLA/LR11 (14, 15), RAP binds calmodulin and is phosphorylated by calmodulin-dependent kinase II and casein kinase II (16). Recently, independent observations have shown the binding of RAP to an approximately 100-kDa protein expressed in osteosarcoma (17) and Chinese hamster ovary cells (18).In the present study we have identified, pu...

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sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD.