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

• Neurotrophin-3 (NT-3) is a cystine knot growth factor that promotes the survival, proliferation, and differentiation of developing neurons and is a potential therapeutic for neurodegenerative diseases [15].
• The authors assessed the effects on Wisconsin Card Sort (WCST) performance and psychiatric symptoms of 30 mg d-amphetamine, a dopamine and norepinephrine agonist, vs placebo in nine patients with schizotypal personality disorder (SPD) [16].
• D-amphetamine challenge effects on Wisconsin Card Sort Test. Performance in schizotypal personality disorder [16].
• Significant improvement in neuropsychological functioning from the first to the second assessment was observed on several tasks, including the following: Trails A and B, Digit Symbol, Judgment of Line Orientation, recognition memory on the Rey Auditory Verbal Learning Test, the Wisconsin Card Sort, and Finger Tapping [17].

Biological context of SORT1

• The findings evidence that the propeptide sterically hinders ligands from gaining access to overlapping binding sites in prosortilin, and that cleavage and release of the propeptide preconditions sortilin for full functional activity [18].
• We report that sorting signals conforming to YXX and dileucine motifs mediate rapid endocytosis of sortilin chimeras, which subsequently travel to the trans-Golgi network, showing little or no recycling [19].
• The luminal N-terminus of sortilin comprises a consensus sequence for cleavage by furin, R41WRR44, which precedes a truncation originally found in sortilin isolated from human brain [18].
• A approximately 95-kDa membrane glycoprotein, designated gp95/sortilin, was purified from human brain extracts by RAP affinity chromatography and cloned in a human cDNA library [20].
• Moreover, addition of preformed complexes of soluble sortilin and proBDNF failed to induce apoptosis of cells coexpressing both sortilin and p75NTR, suggesting that interaction of proBDNF with both receptors on the cell surface is required to initiate cell death [21].

Anatomical context of SORT1

• Gp95/sortilin is expressed in several tissues including brain, spinal cord, and testis [20].
• Expression of a chimeric receptor containing the cytoplasmic tail of gp95/sortilin demonstrates evidence that the tail conveys colocalization with the cation-independent mannose6-phosphate receptor in endosomes and the Golgi compartment [20].
• We have investigated the effect of a non-mutated 32 kDa human recombinant proNGF (rhproNGF) on cultured pig oligodendrocytes which express TrkA, p75NTR and sortilin [22].
• To test this hypothesis, a dominant-negative construct of sortilin and a sortilin small interfering RNA (siRNA) were introduced into COS-7 cells [23].
• Sortilin is upregulated during osteoblastic differentiation of mesenchymal stem cells and promotes extracellular matrix mineralization [3].

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

• Our results showed that both the truncated sortilin and the sortilin siRNA block the traffic of GM2AP and prosaposin to the lysosomal compartment [23].
• Sortilin has a counter effect of promoting osteogenesis by acting as a scavenger of LPL [3].
• The effect of neurotensin on cell migration was blocked by the neurotensin receptor-3 propeptide, a selective ligand of this receptor [31].
• We have found that the reporter protein consisting of the cytoplasmic tail of sortilin and EGFP is co-localized with ectopically expressed Glut4 in the perinuclear compartment of undifferentiated 3T3-L1 cells that do not form insulin-responsive vesicles [30].
• We observed that the effect of neurotensin on the cytokine/chemokine expression is also inhibited by the neurotensin receptor-3 propeptide [32].

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

• We demonstrate, by using RT-PCR, photoaffinity labeling, and Western blot analysis, that the type I neurotensin receptor-3 was the only known neurotensin receptor expressed in these microglial cells and that its activation led to the phosphorylation of both extracellular signal-regulating kinases 1/2 and Akt [31].
• Unlike pineal gland and extracerebral bv, the external carotid artery, an extracranial proximal SCG target, showed no change in NGF following denervation, and mature NT-3 was significantly increased [36].
• Mature NT-3, which was abundant in controls, was significantly decreased in these targets following sympathetic denervation [36].
• Receptor protein expression was analyzed by immunohistochemistry with specific antibodies for the three known neurotensin receptors NTR1, NTR2 and NTR3 [37].
• Examining the protein levels, a strong signal for NTR1 was detected in tumor cells and xenografts and only a weak signal was detected for NTR3 [37].

References