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NEU3 (sialidase 3 (membrane sialidase))

Written2010-06Kazunori Yamaguchi, Taeko Miyagi
Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan (KY); Cancer Glycosylation Research, Tohoku Pharmaceutical University, Sendai 981-8558, Japan (TM)

(Note : for Links provided by Atlas : click)


Alias (NCBI)FLJ12388
HGNC (Hugo) NEU3
HGNC Previous namesialidase 3 (membrane sialidase)
 neuraminidase 3, membrane sialidase
LocusID (NCBI) 10825
Atlas_Id 44505
Location 11q13.4  [Link to chromosome band 11q13]
Location_base_pair Starts at 74988933 and ends at 75010907 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping NEU3.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
NEU3 (11q13.4) / SNTG1 (8q11.21)PEMT (17p11.2) / NEU3 (11q13.4)


Description The NEU3 gene spans 22 kb, consists of 4 exons and 3 introns. It is a member of sialidase family consisting of NEU1, NEU2, NEU3, and NEU4.
Transcription Northern blot analysis reveals 2.5 kb and 7 kb transcripts of NEU3 gene, possessing a common open reading frame of 1284 bp. NEU3 gene expression is diversely regulated by Sp1/Sp3 transcription factors which are recently considered to play critical roles in regulating the transcription of genes involved in cell growth and tumorigenesis.


Description Deduced amino acid sequence of human NEU3 comprises of 428 amino acids and contains RIP box at N-terminal region and three Asp boxes in the center of the amino acid sequence. These motifs are commonly found in sialidases of microorganisms and vertebrates. The RIP motif is a part of active site and mutation of this motif led to decreased enzymatic activity. The Asp box is thought to participate in proper 3D structure formation of NEU3.
Expression The gene is ubiquitously expressed with relatively higher levels in skeletal muscle, heart, and testis. The expression is upregulated during tumorigenesis, neuronal differentiation, T cell activation, and monocyte differentiation. Abnormal upregulation of NEU3 is observed in various human neoplasms including colon, renal, ovarian and prostate cancers, except for the down-regulation in acute lymphoblastic leukemia.
It is interesting to note that the transgenic mice ectopically expressing human NEU3 develop impaired insulin signaling and insulin-resistant diabetes mellitus by 18-22 weeks.
Localisation Biochemical fractionation shows NEU3 to be localized in membrane fractions, especially in raft or caveolae membrane microdomains. In immuno- fluorescence studies, the bovine and mouse Neu3 sialidases are mostly detected on the cell surface, but the human NEU3 may exist also in other cellular membrane components and can mobilize to membrane ruffles together with Rac-1 in response to growth stimuli such as EGF, enhancing cell movement.
Function NEU3 sialidase removes sialic acid moiety of gangliosides. It hardly acts on glycoproteins, oligosaccharides, and an artificial substrate 4MU-NeuAc. NEU3 alters gangliosides composition of tissues and cells, and leads to modulation of signal transduction such as EGFR (epidermal growth factor receptor) and IR (insulin receptor) signaling. Besides, NEU3 has been shown to associate with signaling molecules including EGFR, Grb2, caveolin-1, and Rac. In addition to the catalytic reaction as a sialidase, the interaction with the protein molecules may also give an influence on the NEU3 function. Disturbance of signaling by abnormal upregulation of NEU3 is likely a possible cause of tumorigenesis or diabetes mellitus.
Homology The NEU3 amino acid sequence shows 28% identity to NEU1, 42% to NEU2, and 45% to NEU4. NEU3 orthologs are identified in bovine, mouse, and rat.

Implicated in

Entity Colon cancer
Note NEU3 shows higher enzymatic activity and mRNA level in colon tumors as compared to adjacent normal mucosa. In tumor cells, lactosylceramide, one of the products of NEU3 enzymatic reaction, accumulates in tumor cells. Over expression of NEU3 or exogenous addition of lactosylceramide to the cell culture confer resistance to sodium butyrate-induced apoptosis. On the other hand, silencing of NEU3 by siRNA causes induction of apoptosis in cancer cells accompanied with suppression of EGFR signaling, suggesting that survival of tumor cells is addictive to NEU3 expression. Interestingly, NEU3-knock down in normal cells including primary culture of keratinocytes or fibroblasts does not cause growth arrest nor apoptosis. Transgenic mice ectopically expressing human NEU3 shows upregulation of EGFR signaling, lower induction of apoptosis, and high incidence of ACF (aberrant crypt foci) formation in colon mucosa cells upon administration of azoxymethane (AOM), a carcinogen for colonic tumorigenesis.
Entity Renal cell carcinoma
Note Renal cell carcinoma shows upregulation of NEU3 along with high expression of IL6. IL6 appears to increase NEU3 gene expression in ACHN cells, and the increase brings about enhanced activation of PI3K and Akt upon IL6 administration, resulting in suppression of apoptosis.
Entity Type II diabetes mellitus
Note NEU3 transgenic mice develop impaired insulin signaling and insulin-resistant diabetes mellitus by 18-22 weeks, associated with hyper-insulinemia, islet hyperplasia and increase in the beta-cell mass. As compared to the wild type, insulin-stimulated phosphorylation of the insulin receptor and insulin receptor substrate I is significantly reduced, and activities of phosphatidylinositol 3-kinase and glycogen synthase are also decreased. In muscle extracts, association of tyrosine-phosphorylated NEU3 with Grb2 occurs in response to insulin, together with accumulation of ganglioside GM1 and GM2.

Involvement of NEU3 in cancer progression and development of diabetes suggests that these diseases might be closely related to each other in pathogenesis, given the recent epidemiological reports of higher cancer risk in diabetic patients than in controls.



Up-regulation of plasma membrane-associated ganglioside sialidase (Neu3) in human colon cancer and its involvement in apoptosis suppression.
Kakugawa Y, Wada T, Yamaguchi K, Yamanami H, Ouchi K, Sato I, Miyagi T.
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10718-23. Epub 2002 Jul 29.
PMID 12149448
Down regulation of membrane-bound Neu3 constitutes a new potential marker for childhood acute lymphoblastic leukemia and induces apoptosis suppression of neoplastic cells.
Mandal C, Tringali C, Mondal S, Anastasia L, Chandra S, Venerando B, Mandal C.
Int J Cancer. 2010 Jan 15;126(2):337-49.
PMID 19588508
Human sialidase as a cancer marker.
Miyagi T, Wada T, Yamaguchi K, Shiozaki K, Sato I, Kakugawa Y, Yamanami H, Fujiya T.
Proteomics. 2008 Aug;8(16):3303-11.
PMID 18651674
Aberrant expression of sialidase and cancer progression.
Miyagi T.
Proc Jpn Acad Ser B Phys Biol Sci. 2008;84(10):407-18. (REVIEW)
PMID 19075514
Identification and expression of NEU3, a novel human sialidase associated to the plasma membrane.
Monti E, Bassi MT, Papini N, Riboni M, Manzoni M, Venerando B, Croci G, Preti A, Ballabio A, Tettamanti G, Borsani G.
Biochem J. 2000 Jul 1;349(Pt 1):343-51.
PMID 10861246
Recent development in mammalian sialidase molecular biology.
Monti E, Preti A, Venerando B, Borsani G.
Neurochem Res. 2002 Aug;27(7-8):649-63. (REVIEW)
PMID 12374200
Plasma membrane-associated sialidase (NEU3) promotes formation of colonic aberrant crypt foci in azoxymethane-treated transgenic mice.
Shiozaki K, Yamaguchi K, Sato I, Miyagi T.
Cancer Sci. 2009 Apr;100(4):588-94. Epub 2009 Feb 2.
PMID 19215228
Silencing of membrane-associated sialidase Neu3 diminishes apoptosis resistance and triggers megakaryocytic differentiation of chronic myeloid leukemic cells K562 through the increase of ganglioside GM3.
Tringali C, Lupo B, Cirillo F, Papini N, Anastasia L, Lamorte G, Colombi P, Bresciani R, Monti E, Tettamanti G, Venerando B.
Cell Death Differ. 2009 Jan;16(1):164-74. Epub 2008 Sep 26.
PMID 18820643
Plasma membrane-associated sialidase is up-regulated in renal cell carcinoma and promotes interleukin-6-induced apoptosis suppression and cell motility.
Ueno S, Saito S, Wada T, Yamaguchi K, Satoh M, Arai Y, Miyagi T.
J Biol Chem. 2006 Mar 24;281(12):7756-64. Epub 2006 Jan 20.
PMID 16428383
A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells.
Wada T, Hata K, Yamaguchi K, Shiozaki K, Koseki K, Moriya S, Miyagi T.
Oncogene. 2007 Apr 12;26(17):2483-90. Epub 2007 Mar 5.
PMID 17334392
Cloning, expression, and chromosomal mapping of a human ganglioside sialidase.
Wada T, Yoshikawa Y, Tokuyama S, Kuwabara M, Akita H, Miyagi T.
Biochem Biophys Res Commun. 1999 Jul 22;261(1):21-7.
PMID 10405317
A close association of the ganglioside-specific sialidase Neu3 with caveolin in membrane microdomains.
Wang Y, Yamaguchi K, Wada T, Hata K, Zhao X, Fujimoto T, Miyagi T.
J Biol Chem. 2002 Jul 19;277(29):26252-9. Epub 2002 May 14.
PMID 12011038
Regulation of plasma membrane-associated sialidase NEU3 gene by SP1/SP3 transcription factors.
Yamaguchi K, Koseki K, Shiozaki M, Shimada Y, Wada T, Miyagi T.
Biochem J. 2010 Jun 2. [Epub ahead of print]
PMID 20518744


This paper should be referenced as such :
Yamaguchi, K ; Miyagi, T
NEU3 (sialidase 3 (membrane sialidase))
Atlas Genet Cytogenet Oncol Haematol. 2011;15(3):280-282.
Free journal version : [ pdf ]   [ DOI ]

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  t(8;11)(q11;q13) NEU3/SNTG1
t(11;17)(q13;p11) PEMT/NEU3

External links

HGNC (Hugo)NEU3   7760
Entrez_Gene (NCBI)NEU3    neuraminidase 3
GeneCards (Weizmann)NEU3
Ensembl hg19 (Hinxton)ENSG00000162139 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000162139 [Gene_View]  ENSG00000162139 [Sequence]  chr11:74988933-75010907 [Contig_View]  NEU3 [Vega]
ICGC DataPortalENSG00000162139
TCGA cBioPortalNEU3
AceView (NCBI)NEU3
Genatlas (Paris)NEU3
SOURCE (Princeton)NEU3
Genetics Home Reference (NIH)NEU3
Genomic and cartography
GoldenPath hg38 (UCSC)NEU3  -     chr11:74988933-75010907 +  11q13.4   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NEU3  -     11q13.4   [Description]    (hg19-Feb_2009)
GoldenPathNEU3 - 11q13.4 [CytoView hg19]  NEU3 - 11q13.4 [CytoView hg38]
genome Data Viewer NCBINEU3 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB008185 AK022450 AK290442 AK303540 BC136397
RefSeq transcript (Entrez)NM_001367860 NM_001367861 NM_001367862 NM_001367863 NM_001367864 NM_001367865 NM_001367866 NM_001367867 NM_006656
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)NEU3
Alternative Splicing GalleryENSG00000162139
Gene ExpressionNEU3 [ NCBI-GEO ]   NEU3 [ EBI - ARRAY_EXPRESS ]   NEU3 [ SEEK ]   NEU3 [ MEM ]
Gene Expression Viewer (FireBrowse)NEU3 [ Firebrowse - Broad ]
GenevisibleExpression of NEU3 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)10825
GTEX Portal (Tissue expression)NEU3
Human Protein AtlasENSG00000162139-NEU3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UQ49   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UQ49  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UQ49
Splice isoforms : SwissVarQ9UQ49
Catalytic activity : Enzyme3.2.1.18 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   [ MEROPS ]
Domains : Interpro (EBI)Sialidase    Sialidase-3    Sialidase_fam    Sialidase_sf   
Domain families : Pfam (Sanger)BNR_2 (PF13088)   
Domain families : Pfam (NCBI)pfam13088   
Conserved Domain (NCBI)NEU3
Blocks (Seattle)NEU3
Human Protein Atlas [tissue]ENSG00000162139-NEU3 [tissue]
Peptide AtlasQ9UQ49
IPIIPI00220736   IPI01015066   IPI01011482   IPI00979223   IPI00981583   IPI00982158   IPI00978611   
Protein Interaction databases
IntAct (EBI)Q9UQ49
Ontologies - Pathways
Ontology : AmiGOexo-alpha-sialidase activity  exo-alpha-sialidase activity  exo-alpha-sialidase activity  cytoplasm  plasma membrane  plasma membrane  carbohydrate metabolic process  glycosphingolipid metabolic process  ganglioside catabolic process  ganglioside catabolic process  oligosaccharide catabolic process  oligosaccharide catabolic process  membrane  alpha-sialidase activity  intracellular membrane-bounded organelle  exo-alpha-(2->3)-sialidase activity  exo-alpha-(2->6)-sialidase activity  exo-alpha-(2->8)-sialidase activity  
Ontology : EGO-EBIexo-alpha-sialidase activity  exo-alpha-sialidase activity  exo-alpha-sialidase activity  cytoplasm  plasma membrane  plasma membrane  carbohydrate metabolic process  glycosphingolipid metabolic process  ganglioside catabolic process  ganglioside catabolic process  oligosaccharide catabolic process  oligosaccharide catabolic process  membrane  alpha-sialidase activity  intracellular membrane-bounded organelle  exo-alpha-(2->3)-sialidase activity  exo-alpha-(2->6)-sialidase activity  exo-alpha-(2->8)-sialidase activity  
Pathways : KEGGOther glycan degradation    Sphingolipid metabolism   
REACTOMEQ9UQ49 [protein]
REACTOME PathwaysR-HSA-4085001 [pathway]   
NDEx NetworkNEU3
Atlas of Cancer Signalling NetworkNEU3
Wikipedia pathwaysNEU3
Orthology - Evolution
GeneTree (enSembl)ENSG00000162139
Phylogenetic Trees/Animal Genes : TreeFamNEU3
Homologs : HomoloGeneNEU3
Homology/Alignments : Family Browser (UCSC)NEU3
Gene fusions - Rearrangements
Fusion : MitelmanNEU3/SNTG1 [11q13.4/8q11.21]  
Fusion : MitelmanPEMT/NEU3 [17p11.2/11q13.4]  
Fusion PortalNEU3 11q13.4 SNTG1 8q11.21 BRCA
Fusion PortalPEMT 17p11.2 NEU3 11q13.4 BRCA
Fusion : FusionGDB3.2.1.18   
Fusion : Fusion_HubARRB1--NEU3    NEU3--NDUFV1    NEU3--SNTG1    NEU3--SPCS2    NEU3--UBE2G1    NEU3--ZNF667-AS1    PEMT--NEU3    REEP3--NEU3    SEC13--NEU3    SHANK2--NEU3   
Fusion : QuiverNEU3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNEU3 [hg38]
Exome Variant ServerNEU3
GNOMAD BrowserENSG00000162139
Varsome BrowserNEU3
Genomic Variants (DGV)NEU3 [DGVbeta]
DECIPHERNEU3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisNEU3 
ICGC Data PortalNEU3 
TCGA Data PortalNEU3 
Broad Tumor PortalNEU3
OASIS PortalNEU3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNEU3  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DNEU3
Mutations and Diseases : HGMDNEU3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch NEU3
DgiDB (Drug Gene Interaction Database)NEU3
DoCM (Curated mutations)NEU3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NEU3 (select a term)
NCG6 (London) select NEU3
Cancer3DNEU3(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry NEU3
NextProtQ9UQ49 [Medical]
Target ValidationNEU3
Huge Navigator NEU3 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTD
Pharm GKB GenePA31562
Clinical trialNEU3
canSAR (ICR)NEU3 (select the gene name)
DataMed IndexNEU3
PubMed57 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Jan 1 18:57:11 CET 2021

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