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Gene Review

SORT1  -  sortilin 1

Homo sapiens

Synonyms: 100 kDa NT receptor, Glycoprotein 95, Gp95, LDLCQ6, NT3, ...
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Disease relevance of SORT1

  • We evidenced that three subtypes of neurotensin receptors (NTR1, NTR2 and NTR3) are expressed in U373 glioblastoma cells, at least as far as their mRNAs are concerned [1].
  • METHODS: Here, by an immunoprecipitation approach, we provide biochemical evidence for an endogenous heterodimerization of the G protein-coupled receptor NTR1 with the NTR3 in the human adenocarcinoma cell line HT29 [2].
  • The overexpression of sortilin in hMSCs using an adenovirus vector resulted in the acceleration of mineralization during osteogenic differentiation without affecting alkaline phosphatase activity [3].
  • We devised a simple dorsal root ganglion (DRG) explant culture system, allowing the selection of neuronal populations preferentially responsive to NGF or NT3 [4].
  • The neurotrophins nerve growth factor (NGF) and neurotrophin-3 (NT-3) are potent chemotactic agents for human melanoma cells which express p75(NTR)in vitro [5].

Psychiatry related information on SORT1

  • Patients were assessed using a modified UCLA Parkinson Rating Scale of symptoms and signs, and neuropsychological testing including the Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale, modified Thurstone Word Fluency Test, Wisconsin Card Sort, a test of visual vigilance, and a reaction time task [6].
  • We quantitated CSF levels of NT-3 in elderly patients with major depression (DE) and compared them to patients with Alzheimer's disease (AD), and mentally healthy control subjects (CTR) [7].
  • Neuropsychological test results overall, and Wisconsin Card Sort (Categories Completed) test results in particular, were significantly better after vitamin treatment than after placebo [8].
  • SPD subjects showed significant decrements in performance on the California Verbal Learning Test, a word-list learning measure which requires semantic clustering for more efficient performance, and on the Wisconsin Card Sort Test, a measure requiring concept formation, abstraction, and mental flexibility [9].
  • Regional cerebral blood flow during the Wisconsin Card Sort Test in schizotypal personality disorder [10].

High impact information on SORT1

  • This recognition mechanism provides the basis for regulation of protein transport from the TGN to endosomes/lysosomes, which is shared by sortilin and low-density lipoprotein receptor-related protein [11].
  • Patients with damage to the dorsolateral prefrontal cortex are impaired on cognitive tasks such as the Wisconsin Card Sort Test, the Stroop Test and an anti-saccade paradigm, in which sensory-guided habitual responses must be suppressed in favour of conceptually or memory-guided responses [12].
  • Anterograde axonal transport provides an 'afferent supply' of BDNF and NT-3 to neurons and target tissues, where they function as trophic factors and as neurotransmitters [13].
  • As well, cultures of dermal fibroblasts express neurotrophin-3 (NT-3) mRNA; NT-3 mRNA levels in cultured fibroblasts are modulated by mitogenic stimulation, UV irradiation, and exposure to melanocyte-conditioned medium [14].
  • NT-3 supplementation to cultured melanocytes maintained in Medium 199 alone prevents cell death [14].

Chemical compound and disease context of SORT1


Biological context of SORT1


Anatomical context of SORT1


Associations of SORT1 with chemical compounds

  • A chimeric receptor with the sortilin cytoplasmic domain localizes to the TGN, whereas the chimeric receptor with a mutation at the leucine pair or the acidic cluster is mislocalized to punctate structures reminiscent of early endosomes [24].
  • CONCLUSION: Our results indicate that NT1-11 may act as an endocrine factor to inhibit cortisol secretion through activation of a receptor distinct from the classical NTR1, NTR2, and NTR3 [25].
  • The cellular responses of neurotrophins are mediated by three different types of receptor proteins, the receptor tyrosine kinases of the Trk family, the neurotrophin receptor p75(NTR), which is a member of the tumor necrosis factor receptor (TNFR) superfamily, and sortilin, previously characterized as neurotensin receptor [26].
  • Inoculation of either the NGF- or the NT-3-expressing vectors 3 days before the start of a 6-week course of cisplatin treatment protected against cisplatin-induced neuropathy assessed by electrophysiological, histological and behavioural measures 2 months later [27].
  • These variants show that the amino acid at position 23 (glycine in NGF, threonine in NT-3) is critical for trkC recognition while other residues fine tune the specificity of NT-3 for trkC [28].

Physical interactions of SORT1

  • The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein [19].
  • Mature sorCS1 bound its own propeptide with low affinity but none of the ligands previously shown to interact with sortilin and sorLA [29].
  • Using chemical cross-linking and the yeast two-hybrid system, we show that sortilin interacts with Glut4 and IRAP in the vesicular lumen [30].

Regulatory relationships of SORT1


Other interactions of SORT1

  • Sortilin is synthesized as a proform which, in late Golgi compartments, is converted to the mature receptor by furin-mediated cleavage of a 44 residue N-terminal propeptide [18].
  • The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor [33].
  • The NT3/gp95/sortilin protein is the first transmembrane neuropeptide receptor that does not belong to the superfamily of G-protein-coupled receptors [33].
  • The two human proteins with a VPS10 domain, SorLA and sortilin, both bind neuropeptides [34].
  • The shedding of the NTR3 is sensitive to protein kinase C (PKC) and mitogen-activated protein (MAP) kinase inhibitors and to 1,10-phenanthroline and BB3103, suggesting the activation of zinc-metalloproteases and the ADAM10 (a desintegrin and metalloprotease) [35].

Analytical, diagnostic and therapeutic context of SORT1


  1. The in vitro influences of neurotensin on the motility characteristics of human U373 glioblastoma cells. Servotte, S., Camby, I., Debeir, O., Deroanne, C., Lambert, C.A., Lapi??re, C.M., Kiss, R., Nusgens, B., Decaestecker, C. Neuropathol. Appl. Neurobiol. (2006) [Pubmed]
  2. Neurotensin receptor-1 and -3 complex modulates the cellular signaling of neurotensin in the HT29 cell line. Martin, S., Navarro, V., Vincent, J.P., Mazella, J. Gastroenterology (2002) [Pubmed]
  3. Sortilin is upregulated during osteoblastic differentiation of mesenchymal stem cells and promotes extracellular matrix mineralization. Maeda, S., Nobukuni, T., Shimo-Onoda, K., Hayashi, K., Yone, K., Komiya, S., Inoue, I. J. Cell. Physiol. (2002) [Pubmed]
  4. Identification of genes differentially expressed by nerve growth factor- and neurotrophin-3-dependent sensory neurons. Friedel, R.H., Schnürch, H., Stubbusch, J., Barde, Y.A. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  5. Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin. Shonukan, O., Bagayogo, I., McCrea, P., Chao, M., Hempstead, B. Oncogene (2003) [Pubmed]
  6. A crossover trial of bromocriptine in the treatment of vascular dementia. Nadeau, S.E., Malloy, P.F., Andrew, M.E. Ann. Neurol. (1988) [Pubmed]
  7. Increased cerebrospinal fluid levels of neurotrophin 3 (NT-3) in elderly patients with major depression. Hock, C., Heese, K., Müller-Spahn, F., Huber, P., Riesen, W., Nitsch, R.M., Otten, U. Mol. Psychiatry (2000) [Pubmed]
  8. Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Levine, J., Stahl, Z., Sela, B.A., Ruderman, V., Shumaico, O., Babushkin, I., Osher, Y., Bersudsky, Y., Belmaker, R.H. Biol. Psychiatry (2006) [Pubmed]
  9. Neuropsychological dysfunction in schizotypal personality disorder: a profile analysis. Voglmaier, M.M., Seidman, L.J., Salisbury, D., McCarley, R.W. Biol. Psychiatry (1997) [Pubmed]
  10. Regional cerebral blood flow during the Wisconsin Card Sort Test in schizotypal personality disorder. Buchsbaum, M.S., Trestman, R.L., Hazlett, E., Siegel, B.V., Schaefer, C.H., Luu-Hsia, C., Tang, C., Herrera, S., Solimando, A.C., Losonczy, M., Serby, M., Silverman, J., Siever, L.J. Schizophr. Res. (1997) [Pubmed]
  11. Structural basis for recognition of acidic-cluster dileucine sequence by GGA1. Shiba, T., Takatsu, H., Nogi, T., Matsugaki, N., Kawasaki, M., Igarashi, N., Suzuki, M., Kato, R., Earnest, T., Nakayama, K., Wakatsuki, S. Nature (2002) [Pubmed]
  12. Prefrontal neuronal activity in rhesus monkeys performing a delayed anti-saccade task. Funahashi, S., Chafee, M.V., Goldman-Rakic, P.S. Nature (1993) [Pubmed]
  13. Neurotrophin trafficking by anterograde transport. Altar, C.A., DiStefano, P.S. Trends Neurosci. (1998) [Pubmed]
  14. The trk family of receptors mediates nerve growth factor and neurotrophin-3 effects in melanocytes. Yaar, M., Eller, M.S., DiBenedetto, P., Reenstra, W.R., Zhai, S., McQuaid, T., Archambault, M., Gilchrest, B.A. J. Clin. Invest. (1994) [Pubmed]
  15. Crystal structure of neurotrophin-3 homodimer shows distinct regions are used to bind its receptors. Butte, M.J., Hwang, P.K., Mobley, W.C., Fletterick, R.J. Biochemistry (1998) [Pubmed]
  16. D-amphetamine challenge effects on Wisconsin Card Sort Test. Performance in schizotypal personality disorder. Siegel, B.V., Trestman, R.L., O'Flaithbheartaigh, S., Mitropoulou, V., Amin, F., Kirrane, R., Silverman, J., Schmeidler, J., Keefe, R.S., Siever, L.J. Schizophr. Res. (1996) [Pubmed]
  17. Evaluation of the stability of neuropsychological functioning after acute episodes of schizophrenia: one-year followup study. Sweeney, J.A., Haas, G.L., Keilp, J.G., Long, M. Psychiatry research. (1991) [Pubmed]
  18. Propeptide cleavage conditions sortilin/neurotensin receptor-3 for ligand binding. Munck Petersen, C., Nielsen, M.S., Jacobsen, C., Tauris, J., Jacobsen, L., Gliemann, J., Moestrup, S.K., Madsen, P. EMBO J. (1999) [Pubmed]
  19. The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein. Nielsen, M.S., Madsen, P., Christensen, E.I., Nykjaer, A., Gliemann, J., Kasper, D., Pohlmann, R., Petersen, C.M. EMBO J. (2001) [Pubmed]
  20. Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. Petersen, C.M., Nielsen, M.S., Nykjaer, A., Jacobsen, L., Tommerup, N., Rasmussen, H.H., Roigaard, H., Gliemann, J., Madsen, P., Moestrup, S.K. J. Biol. Chem. (1997) [Pubmed]
  21. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. Teng, H.K., Teng, K.K., Lee, R., Wright, S., Tevar, S., Almeida, R.D., Kermani, P., Torkin, R., Chen, Z.Y., Lee, F.S., Kraemer, R.T., Nykjaer, A., Hempstead, B.L. J. Neurosci. (2005) [Pubmed]
  22. Mature pig oligodendrocytes rapidly process human recombinant pro-nerve growth factor and do not undergo cell death. Althaus, H.H., Klöppner, S. J. Neurochem. (2006) [Pubmed]
  23. The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin. Lefrancois, S., Zeng, J., Hassan, A.J., Canuel, M., Morales, C.R. EMBO J. (2003) [Pubmed]
  24. Golgi-localizing, gamma-adaptin ear homology domain, ADP-ribosylation factor-binding (GGA) proteins interact with acidic dileucine sequences within the cytoplasmic domains of sorting receptors through their Vps27p/Hrs/STAM (VHS) domains. Takatsu, H., Katoh, Y., Shiba, Y., Nakayama, K. J. Biol. Chem. (2001) [Pubmed]
  25. The N-terminal neurotensin fragment, NT1-11, inhibits cortisol secretion by human adrenocortical cells. Sicard, F., Contesse, V., Lefebvre, H., Ait-Ali, D., Gras, M., Cartier, D., Decker, A., Chartrel, N., Anouar, Y., Vaudry, H., Delarue, C. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  26. The dual nature of neurotrophins. Schweigreiter, R. Bioessays (2006) [Pubmed]
  27. Protective effect of herpes simplex virus-mediated neurotrophin gene transfer in cisplatin neuropathy. Chattopadhyay, M., Goss, J., Wolfe, D., Goins, W.C., Huang, S., Glorioso, J.C., Mata, M., Fink, D.J. Brain (2004) [Pubmed]
  28. Specificity determinants in neurotrophin-3 and design of nerve growth factor-based trkC agonists by changing central beta-strand bundle residues to their neurotrophin-3 analogs. Urfer, R., Tsoulfas, P., O'Connell, L., Presta, L.G. Biochemistry (1997) [Pubmed]
  29. Characterization of sorCS1, an alternatively spliced receptor with completely different cytoplasmic domains that mediate different trafficking in cells. Hermey, G., Keat, S.J., Madsen, P., Jacobsen, C., Petersen, C.M., Gliemann, J. J. Biol. Chem. (2003) [Pubmed]
  30. The Luminal Vps10p Domain of Sortilin Plays the Predominant Role in Targeting to Insulin-responsive Glut4-containing Vesicles. Shi, J., Kandror, K.V. J. Biol. Chem. (2007) [Pubmed]
  31. Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of human microglia. Martin, S., Vincent, J.P., Mazella, J. J. Neurosci. (2003) [Pubmed]
  32. Neurotensin and the neurotensin receptor-3 in microglial cells. Martin, S., Dicou, E., Vincent, J.P., Mazella, J. J. Neurosci. Res. (2005) [Pubmed]
  33. The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. Mazella, J., Zsürger, N., Navarro, V., Chabry, J., Kaghad, M., Caput, D., Ferrara, P., Vita, N., Gully, D., Maffrand, J.P., Vincent, J.P. J. Biol. Chem. (1998) [Pubmed]
  34. The genes for the human VPS10 domain-containing receptors are large and contain many small exons. Hampe, W., Rezgaoui, M., Hermans-Borgmeyer, I., Schaller, H.C. Hum. Genet. (2001) [Pubmed]
  35. Shedding of the luminal domain of the neurotensin receptor-3/sortilin in the HT29 cell line. Navarro, V., Vincent, J.P., Mazella, J. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  36. Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input. Randolph, C.L., Bierl, M.A., Isaacson, L.G. Brain Res. (2007) [Pubmed]
  37. Neurotensin receptors in adeno- and squamous cell carcinoma. Haase, C., Bergmann, R., Oswald, J., Zips, D., Pietzsch, J. Anticancer Res. (2006) [Pubmed]
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