| Note | SNX3 belongs to Sorting Nexins family consisting of more than 30 members (P.J. Cullen, 2008). SNX family members are classified according to their domain structures. Members of sorting nexins have a combination of the following domains: Bin/Rvs/Amphiphysin domain (BAR), Phox homology domain (PX), 4.1/Ezrin/Radixin/Moesin-like domain (FERM), PXA (PX-associated domain A), RGS (Regulator of G-protein signaling), PXC (PX- associated domain C) and MIT (microtubule-interacting and trafficking molecule domain) (R.D. Teasdale, 2012). SNX3 has only the PX domain. |
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| | Figure 3. SNX3 consists of only the PX domain. |
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| Description | SNX3 is a small protein of 162 amino acids. Molecular weight of the protein is 18,762 Da. |
| Expression | SNX3 is expressed in brain, eye, endocrine tissues, lung, proximal digestive tract, gastrointestinal tract, liver and gallbladder, pancreas, kidney and urinary bladder, male tissues, female tissues, muscle tissues, adipose and soft tissue, skin, bone marrow and lymphoid tissues and blood. (The Human Protein Atlas, http://www.proteinatlas.org/). |
| Localisation | SNX3 protein is mostly localized to the endosomes with the retromer complex (M. Harterink, 2011). |
| Function | SNX3 functions within the retromer complex. Among other members of the nexins, only SNX3 is indispensable for recognition and recycling of WLS (Wntless) in Drosophila (P. Zhang, 2011). SNX3 is required for the binding of VPS26 and VPS35 association complex to endosomal membranes (M. Lucas, 2016). For efficient recruitment of retromer proteins to the endosomes, SNX3 binding to PI3Ps of endosomes through its PX domain. RAB7A GTPase is also recruited to the endosome. Consequently, VPS35, VPS26 and VPS29 trimer interacts with the endosome. SNX3 almost functions as a bridge by interacting with the PI3Ps and the VPS trimer. Binding of retromer to SNX3 causes a conformational change on retromer complex, which creates a binding surface for cargo proteins (M. Gallon, 2015). |
| Homology | The SNX3 gene is conserved among species such as chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, frog, zebrafish and yeast.(NCBI). |
| Note | SNX3 has been implicated in diverse diseases. |
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| Entity | Split Hand/Foot Malformation (SHFM) |
| Note | SNX3 locus has been implicated to be a possibly important region for SHFM (Duijf et.al., 2003; Braverman et.al., 1993; Gurrieri et.al., 1995; Correa-Cerro et.al., 1996). 6q21 region is also associated with some other malformations like microcephaly, microphthalmia, ectrodactyly and prognathism (Duijf et.el., 2003 and Vervoort et.al., 2002). |
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| Entity | MMEP (Microcephaly, microphthalmia, ectrodactyly and prognathism) |
| Note | SNX3 disruption on 6q21 was reported in a patient with MMEP and t(6;13)(q21;q12) but SNX3 mutations were not identified in other MMEP patients, which may suggest involvement of other genes (Vervoort et.al., 2002). |
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| Entity | Autosomal Dominant Polycyctic Kidney Disease (ADPKD). |
| Note | Polycystin-1 ( PKD1) and Polycystin-2 ( PKD2) are plasma membrane receptor-ion channel proteins implicated in ADPKD. SNX3 has a role in endocytosis of PKD2. It was reported that compounds that downregulate SNX3 expression or which inhibit its function could have therapeutic benefits for ADPKD patients. (Feng et al.,2017). |
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| Entity | Epidermoid Carcinoma |
| Note | SNX3 has a role in endosomal trafficking of TFRC (transferrin receptor) (Chen et al., 2013). Aspirin is suggested to regulate the recycling of TFRC and possibly EGFR in epidermoid carcinoma cell lines (A-431) by delaying their recycling and causing their accumulation in early endosomes (Chiow et al., 2012). |
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| Entity | Acute Lymphoblastic Leukemia |
| Note | Dexamethasone (DEXA) is a frequently preferred chemotherapeutic drug for childhood acute lymphoblastic leukemia (ALL) patients, however, drug resistance is a problem. Proteomic studies revealed that SNX3 is expressed differentially between DEXA treated DEXA- resistant cell line (REH) and non-DEXA treated REH. In REH cells, SNX3 expression is down-regulated. Additionally, both in high risk and standard risk group ALL patients, SNX3 downregulation is observed when compared to normal control group. Downregulation of SNX3 may be associated with both chemoresistance and tumorigenesis (Dehghan-Nayeri et al., 2017). |
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| Entity | Alzheimier Disease |
| Note | Neurotoxic amyloid β peptide (Aβ) with the processing of amyloid precursor protein ( APP) by proteolytic cleavage has the leading role in Alzheimier disease (AD) pathogenesis (Vardarajan, 2012). Retromer complex including SNX3 provides proper trafficking of APP, which is necessary to prevent abnormal production of Aβ peptide. It was reported that SNX3 has AD related SNPs. Overexpression of SNX3 in HEK293T showed reduction in the secreted Aβ level. Regulation of Aβ peptide with controlling APP may make SNX3 a candidate for AD treatment (Xu, 2018). |
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| Entity | Parkinson's Disease |
| Note | Alpha-synuclein ( SNCA) protein has a role in the iron metabolism and expression. High expression level of alpha-synuclein in dopaminergic neurons causes Parkinson's Disease. In yeast, Fet3/Ftr1 complex has role in external iron intake. When the external iron concentration is low, interaction of Ftr1 C-terminus with Snx3-retromer complex provides retrograde transport of the complex. Under the condition of high external iron concentration, internalized complex is degraded. Interestingly, action of the α-syn mimics the high iron concentration response and leads to degradation of Fet3/Ftr1 via hindering the Snx3 interaction with early endosome and hence, cellular iron homeostasis is disrupted (Patel, 2018). |
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| Entity | Anemia |
| Note | SNX3 functions in the recycling of TFRC (transferrin receptor). Knockdown of snx3 in zebrafish embryos results in intensive anemia. Consistently, silencing of Snx3 in mouse primary fatal liver cells causes reduced total hemoglobin content (Chen et al., 2013). |
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| Entity | Infection |
| Note | SNX3 has a role in Salmonella typhimirium infection in human cells. S.typhimirium is an intracellular pathogen and resides in Salmonella containing vesicles (SCVs) in cell. During infection, SNX3 functions in the tubule formation from the SCVs during Salmonella invasion (Braun et al., 2010). |
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| Sorting nexin 3 (SNX3) is a component of a tubular endosomal network induced by Salmonella and involved in maturation of the Salmonella-containing vacuole |
| Braun V, Wong A, Landekic M, Hong WJ, Grinstein S, Brumell JH |
| Cell Microbiol 2010 Sep 1;12(9):1352-67 |
| PMID 20482551 |
| |
| The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data |
| Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N |
| Cancer Discov 2012 May;2(5):401-4 |
| PMID 22588877 |
| |
| Snx3 regulates recycling of the transferrin receptor and iron assimilation |
| Chen C, Garcia-Santos D, Ishikawa Y, Seguin A, Li L, Fegan KH, Hildick-Smith GJ, Shah DI, Cooney JD, Chen W, King MJ, Yien YY, Schultz IJ, Anderson H, Dalton AJ, Freedman ML, Kingsley PD, Palis J, Hattangadi SM, Lodish HF, Ward DM, Kaplan J, Maeda T, Ponka P, Paw BH |
| Cell Metab 2013 Mar 5;17(3):343-52 |
| PMID 23416069 |
| |
| SNX3-dependent regulation of epidermal growth factor receptor (EGFR) trafficking and degradation by aspirin in epidermoid carcinoma (A-431) cells |
| Chiow KH, Tan Y, Chua RY, Huang D, Ng ML, Torta F, Wenk MR, Wong SH |
| Cell Mol Life Sci 2012 May;69(9):1505-21 |
| PMID 22159558 |
| |
| Interstitial deletion 6q16 |
| Correa-Cerro L, Garcíaz-Cruz D, Díaz-Castaños L, Figuera LE, Sanchez-Corona J |
| 2q22 2 in a child with ectrodactyly |
| PMID 8766142 |
| |
| Endosomal sorting and signalling: an emerging role for sorting nexins |
| Cullen PJ |
| Nat Rev Mol Cell Biol 2008 Jul;9(7):574-82 |
| PMID 18523436 |
| |
| Identification of potential predictive markers of dexamethasone resistance in childhood acute lymphoblastic leukemia |
| Dehghan-Nayeri N, Rezaei-Tavirani M, Omrani MD, Gharehbaghian A, Goudarzi Pour K, Eshghi P |
| J Cell Commun Signal 2017 Jun;11(2):137-145 |
| PMID 27778231 |
| |
| Pathogenesis of split-hand/split-foot malformation |
| Duijf PH, van Bokhoven H, Brunner HG |
| Hum Mol Genet 2003 Apr 1;12 Spec No 1:R51-60 |
| PMID 12668597 |
| |
| The Sorting Nexin 3 Retromer Pathway Regulates the Cell Surface Localization and Activity of a Wnt-Activated Polycystin Channel Complex |
| Feng S, Streets AJ, Nesin V, Tran U, Nie H, Onopiuk M, Wessely O, Tsiokas L, Ong ACM |
| J Am Soc Nephrol 2017 Oct;28(10):2973-2984 |
| PMID 28620080 |
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| Retromer and sorting nexins in endosomal sorting |
| Gallon M, Cullen PJ |
| Biochem Soc Trans 2015 Feb;43(1):33-47 |
| PMID 25619244 |
| |
| Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal |
| Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N |
| Sci Signal 2013 Apr 2;6(269):pl1 |
| PMID 23550210 |
| |
| Ulnar ray defect in an infant with a 6q21;7q31 |
| Gurrieri F, Cammarata M, Avarello RM, Genuardi M, Pomponi MG, Neri G, Giuffrè L |
| 2 translocation: further evidence for the existence of a limb defect gene in 6q21 Am J Med Genet |
| PMID 7726229 |
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| A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion |
| Harterink M, Port F, Lorenowicz MJ, McGough IJ, Silhankova M, Betist MC, van Weering JRT, van Heesbeen RGHP, Middelkoop TC, Basler K, Cullen PJ, Korswagen HC |
| Nat Cell Biol 2011 Jul 3;13(8):914-923 |
| PMID 21725319 |
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| Structural Mechanism for Cargo Recognition by the Retromer Complex |
| Lucas M, Gershlick DC, Vidaurrazaga A, Rojas AL, Bonifacino JS, Hierro A |
| Cell 2016 Dec 1;167(6):1623-1635 |
| PMID 27889239 |
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| Alpha-synuclein inhibits Snx3-retromer-mediated retrograde recycling of iron transporters in S |
| Patel D, Xu C, Nagarajan S, Liu Z, Hemphill WO, Shi R, Uversky VN, Caldwell GA, Caldwell KA, Witt SN |
| cerevisiae and C elegans models of Parkinson's disease |
| PMID 29452354 |
| |
| The use and misuse of thyroid hormone |
| Roti E, Minelli R, Gardini E, Braverman LE |
| Endocr Rev 1993 Aug;14(4):401-23 |
| PMID 8223339 |
| |
| Insights into the PX (phox-homology) domain and SNX (sorting nexin) protein families: structures, functions and roles in disease |
| Teasdale RD, Collins BM |
| Biochem J 2012 Jan 1;441(1):39-59 |
| PMID 22168438 |
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| Identification of Alzheimer disease-associated variants in genes that regulate retromer function |
| Vardarajan BN, Bruesegem SY, Harbour ME, Inzelberg R, Friedland R, St George-Hyslop P, Seaman MN, Farrer LA |
| Neurobiol Aging 2012 Sep;33(9):2231 |
| PMID 22673115 |
| |
| Mutations of RPGR in X-linked retinitis pigmentosa (RP3) |
| Vervoort R, Wright AF |
| Hum Mutat 2002 May;19(5):486-500 |
| PMID 11968081 |
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| Sorting nexin 3 (SNX3) is disrupted in a patient with a translocation t(6;13)(q21;q12) and microcephaly, microphthalmia, ectrodactyly, prognathism (MMEP) phenotype |
| Vervoort VS, Viljoen D, Smart R, Suthers G, DuPont BR, Abbott A, Schwartz CE |
| J Med Genet 2002 Dec;39(12):893-9 |
| PMID 12471201 |
| |
| Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Internalization of Amyloid Precursor Protein |
| Xu S, Nigam SM, Brodin L |
| Neurodegener Dis 2018;18(1):26-37 |
| PMID 29414832 |
| |
| SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless |
| Zhang P, Wu Y, Belenkaya TY, Lin X |
| Cell Res 2011 Dec;21(12):1677-90 |
| PMID 22041890 |
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