The Plasma Membrane Sialidase NEU3 Regulates the Malignancy of Renal Carcinoma Cells by Controlling β1 Integrin Internalization and Recycling

Tringali, Cristina; Lupo, Barbara; Silvestri, Ilaria; Papini, Nadia; Anastasia, Luigi; Tettamanti, Guido; Venerando, Bruno

doi:10.1074/jbc.m112.407718

Cited by 59 publications

(38 citation statements)

References 44 publications

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“…Lately, this group also indicated that expression of ST6Gal I regulates cancer stem cell resistance to chemotherapy with irinocetan (17). Importantly, the sialidase NEU3 has recently been found to mediate resistance to the topoisomerase inhibitor etoposide, potentially by affecting surface expression of b1-integrins and increased FAK/AKT signaling (34).…”

Section: Sialic Acids and Resistance To Cancer Therapymentioning

confidence: 96%

Sialic Acids Sweeten a Tumor's Life

et al. 2014

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Over four decades ago, specific tumor characteristics were ascribed to the increased expression of sialic acid sugars on the surface of cancer cells, and this led to the definition of sialic acids as potential therapeutic targets. Recent advances in glycobiology and cancer research have defined the key processes underlying aberrant expression of sialic acids in cancer, and its consequences, more precisely. These consequences include effects on tumor growth, escape from apoptosis, metastasis formation, and resistance to therapy. Collectively, these novel insights provide further rationale for the design and development of therapeutic approaches that interfere with excessively high expression of sialic acids in cancer cells. Strategies to target aberrant sialylation in cancer, however, have evolved comparatively slowly. Here, we review recent findings that emphasize the detrimental effects of hypersialylation on multiple aspects of tumor growth and behavior. We also discuss novel therapeutic strategies. Cancer Res; 74(12); 3199-204. Ó2014 AACR.

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Section: Sialic Acids and Resistance To Cancer Therapymentioning

confidence: 96%

Sialic Acids Sweeten a Tumor's Life

et al. 2014

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“…NEU3 physically and/or functionally interacts with caveolin-1 (67), Rac1 (68), integrins ␤1 (59) and ␤4 (26), Grb-2 (52), Akt (59), focal adhesion kinase (59), and Ras (62). NEU3 strongly regulates insulin (52,69) and EGFR (34,38,59,62,68) signaling pathways and alters expression of multiple metalloproteinases (MMPs), including MMP-2, MMP-7, and MMP-9 (24,29,43,59). In conclusion, this report demonstrates that human airway ECs express catalytically active NEU3 sialidase and implicate NEU3 in multiple biological processes within human airway epithelia.…”

Section: Discussionmentioning

confidence: 99%

“…The caveolin-binding sequence promotes NEU3 association with the scaffolding protein, caveolin-1, and its sequestration within microdomains in the plasma membrane (67), in close proximity to a variety of signaling elements (44). In fact, NEU3 influences signaling events coupled to multiple cell surface receptors (37), including the epidermal growth factor receptor (EGFR) (34,38,59,62,68), the insulin receptor (52,69), Toll-like receptor (TLR)4 (5), and the TrkA receptor (24). NEU3 differentially hydrolyzes SA residues in various gangliosides, exerting greater activity for GM3, GD1a, GD1b, and GD3 but far less, if any, activity for GM1 and GM2 (36,63).…”

mentioning

confidence: 99%

Human airway epithelia express catalytically active NEU3 sialidase

Lillehoj

Hyun²,

Feng

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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acids on glycoconjugates play a pivotal role in many biological processes. In the airways, sialylated glycoproteins and glycolipids are strategically positioned on the plasma membranes of epithelia to regulate receptor-ligand, cell-cell, and host-pathogen interactions at the molecular level. We now demonstrate, for the first time, sialidase activity for ganglioside substrates in human airway epithelia. Of the four known mammalian sialidases, NEU3 has a substrate preference for gangliosides and is expressed at mRNA and protein levels at comparable abundance in epithelia derived from human trachea, bronchi, small airways, and alveoli. In small airway and alveolar epithelia, NEU3 protein was immunolocalized to the plasma membrane, cytosolic, and nuclear subcellular fractions. Small interfering RNA-induced silencing of NEU3 expression diminished sialidase activity for a ganglioside substrate by Ͼ70%. NEU3 immunostaining of intact human lung tissue could be localized to the superficial epithelia, including the ciliated brush border, as well as to nuclei. However, NEU3 was reduced in subepithelial tissues. These results indicate that human airway epithelia express catalytically active NEU3 sialidase.

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“…In fact, the overexpression of the human ortholog NEU3 in a mouse model induces the development of insulin-resistant diabetes mellitus (11). Also, an excessive up-regulation of NEU3 has been detected in various neoplasms, including colon (12), renal (13,14), ovarian (15), melanoma (16), and prostate cancers (17), although a down-regulation of the enzyme has been observed in acute lymphoblastic leukemia (18).…”

mentioning

confidence: 99%

NEU3 Sialidase Protein Interactors in the Plasma Membrane and in the Endosomes

Cirillo

Ghiroldi

Fania

et al. 2016

Journal of Biological Chemistry

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NEU3 sialidase has been shown to be a key player in many physio-and pathological processes, including cell differentiation, cellular response to hypoxic stress, and carcinogenesis. The enzyme, peculiarly localized on the outer leaflet of the plasma membrane, has been shown to be able to remove sialic acid residues from the gangliosides present on adjacent cells, thus creating cell to cell interactions. Nonetheless, herein we report that the enzyme localization is dynamically regulated between the plasma membrane and the endosomes, where a substantial amount of NEU3 is stored with low enzymatic activity. However, under opportune stimuli, NEU3 is shifted from the endosomes to the plasma membrane, where it greatly increases the sialidase activity. Finally, we found that NEU3 possesses also the ability to interact with specific proteins, many of which are different in each cell compartment. They were identified by mass spectrometry, and some selected ones were also confirmed by cross-immunoprecipitation with the enzyme, supporting NEU3 involvement in the cell stress response, protein folding, and intracellular trafficking.

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The Plasma Membrane Sialidase NEU3 Regulates the Malignancy of Renal Carcinoma Cells by Controlling β1 Integrin Internalization and Recycling

Cited by 59 publications

References 44 publications

Sialic Acids Sweeten a Tumor's Life

Sialic Acids Sweeten a Tumor's Life

Human airway epithelia express catalytically active NEU3 sialidase

NEU3 Sialidase Protein Interactors in the Plasma Membrane and in the Endosomes

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