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| 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. |
| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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