NEU3 (sialidase 3 (membrane sialidase))

2010-06-01   Kazunori 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)

Identity

HGNC
LOCATION
11q13.4
LOCUSID
ALIAS
SIAL3
FUSION GENES

DNA/RNA

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.

Proteins

Atlas Image

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 name
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 name
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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
121494482002Up-regulation of plasma membrane-associated ganglioside sialidase (Neu3) in human colon cancer and its involvement in apoptosis suppression.Kakugawa Y et al
195885082010Down regulation of membrane-bound Neu3 constitutes a new potential marker for childhood acute lymphoblastic leukemia and induces apoptosis suppression of neoplastic cells.Mandal C et al
186516742008Human sialidase as a cancer marker.Miyagi T et al
190755142008Aberrant expression of sialidase and cancer progression.Miyagi T et al
108612462000Identification and expression of NEU3, a novel human sialidase associated to the plasma membrane.Monti E et al
123742002002Recent development in mammalian sialidase molecular biology.Monti E et al
192152282009Plasma membrane-associated sialidase (NEU3) promotes formation of colonic aberrant crypt foci in azoxymethane-treated transgenic mice.Shiozaki K et al
188206432009Silencing 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 et al
164283832006Plasma membrane-associated sialidase is up-regulated in renal cell carcinoma and promotes interleukin-6-induced apoptosis suppression and cell motility.Ueno S et al
173343922007A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells.Wada T et al
104053171999Cloning, expression, and chromosomal mapping of a human ganglioside sialidase.Wada T et al
120110382002A close association of the ganglioside-specific sialidase Neu3 with caveolin in membrane microdomains.Wang Y et al
205187442010Regulation of plasma-membrane-associated sialidase NEU3 gene by Sp1/Sp3 transcription factors.Yamaguchi K et al

Other Information

Locus ID:

NCBI: 10825
MIM: 604617
HGNC: 7760
Ensembl: ENSG00000162139

Variants:

dbSNP: 10825
ClinVar: 10825
TCGA: ENSG00000162139
COSMIC: NEU3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000162139ENST00000294064Q9UQ49
ENSG00000162139ENST00000294064A0A024R5N6
ENSG00000162139ENST00000526068E9PI40
ENSG00000162139ENST00000529024E9PMZ3
ENSG00000162139ENST00000531509Q9UQ49
ENSG00000162139ENST00000531509A0A024R5N6
ENSG00000162139ENST00000531619E9PR25
ENSG00000162139ENST00000532963E9PMZ3
ENSG00000162139ENST00000534628E9PNK1

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Other glycan degradationKEGGko00511
Sphingolipid metabolismKEGGko00600
Other glycan degradationKEGGhsa00511
Sphingolipid metabolismKEGGhsa00600
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Asparagine N-linked glycosylationREACTOMER-HSA-446203
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent proteinREACTOMER-HSA-446193
Synthesis of substrates in N-glycan biosythesisREACTOMER-HSA-446219
Sialic acid metabolismREACTOMER-HSA-4085001
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Sphingolipid metabolismREACTOMER-HSA-428157
Glycosphingolipid metabolismREACTOMER-HSA-1660662

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA10832corticosteroidsChemicalVariantAnnotationnot associatedPD26644204
PA443937Drug ToxicityDiseaseVariantAnnotationnot associatedPD26644204
PA446155Precursor Cell Lymphoblastic Leukemia-LymphomaDiseaseVariantAnnotationnot associatedPD26644204
PA452621antineoplastic agentsChemicalVariantAnnotationnot associatedPD26644204

References

Pubmed IDYearTitleCitations
121494482002Up-regulation of plasma membrane-associated ganglioside sialidase (Neu3) in human colon cancer and its involvement in apoptosis suppression.46
120110382002A close association of the ganglioside-specific sialidase Neu3 with caveolin in membrane microdomains.34
170281992007Sialidase expression in activated human T lymphocytes influences production of IFN-gamma.31
127302042003Overexpression of plasma membrane-associated sialidase attenuates insulin signaling in transgenic mice.27
189533562008CD15 expression in human myeloid cell differentiation is regulated by sialidase activity.26
173343922007A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells.25
164283832006Plasma membrane-associated sialidase is up-regulated in renal cell carcinoma and promotes interleukin-6-induced apoptosis suppression and cell motility.23
186516742008Human sialidase as a cancer marker.22
158851032005Differential expression of endogenous sialidases of human monocytes during cellular differentiation into macrophages.20
162419052006Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signalling.19

Citation

Kazunori Yamaguchi ; Taeko Miyagi

NEU3 (sialidase 3 (membrane sialidase))

Atlas Genet Cytogenet Oncol Haematol. 2010-06-01

Online version: http://atlasgeneticsoncology.org/gene/44505/neu3