Exo-alpha-sialidase that catalyzes the hydrolytic cleavage of the terminal sialic acid (N-acetylneuraminic acid, Neu5Ac) of a glycan moiety in the catabolism of glycolipids, glycoproteins and oligosacharides. Displays high catalytic efficiency for gangliosides including alpha-(2->3)-sialylated GD1a and GM3 and alpha-(2->8)-sialylated GD3 (PubMed:17708748, PubMed:10713120, PubMed:11696012, PubMed:14970224). Plays a role in the regulation of transmembrane signaling through the modulation of ganglioside content of the lipid bilayer and by direct interaction with signaling receptors, such as EGFR. Desialylates EGFR and activates downstream signaling in proliferating cells. Contributes to clathrin-mediated endocytosis by regulating sorting of endocytosed receptors to early and recycling endosomes (By similarity). Hydrolysis of alpha-(2->3)-, alpha-(2->6)-, alpha-(2->8)- glycosidic linkages of terminal sialic acid residues in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates. ganglioside GD1a + H2O = ganglioside GM1 + N-acetylneuraminate ganglioside GD1a (d18:1(4E)) + H2O = ganglioside GM1 (d18:1(4E)) + N-acetylneuraminate ganglioside GD1b + H2O = ganglioside GM1 + N-acetylneuraminate ganglioside GD1b (d18:1(4E)) + H2O = ganglioside GM1 (d18:1(4E)) + N-acetylneuraminate ganglioside GD3 + H2O = ganglioside GM3 + N-acetylneuraminate ganglioside GD3 (d18:1(4E)) + H2O = ganglioside GM3 (d18:1(4E)) + N-acetylneuraminate ganglioside GM3 + H2O = beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1<->1)-ceramide + N-acetylneuraminate ganglioside GM1 + H2O = ganglioside GA1 + N-acetylneuraminate ganglioside GM1 (d18:1(4E)) + H2O = ganglioside GA1 (d18:1(4E)) + N-acetylneuraminate ganglioside GM2 (d18:1(4E)) + H2O = ganglioside GA2 (d18:1(4E)) + N-acetylneuraminate ganglioside GM3 (d18:1(4E)) + H2O = a beta-D-Gal-(1->4)-beta-D-Glc-(1<->1)-Cer(d18:1(4E)) + N-acetylneuraminate ganglioside GT1b + H2O = ganglioside GD1b + N-acetylneuraminate Optimum pH is 3.8. Interacts with CAV1; this interaction enhances NEU3 sialidase activity within caveola. Interacts with EGFR; this interaction mediates desialylation of EGFR and enhances downstream signaling. Associates with the external leaflet of the plasma membrane (PubMed:17708748). S-acylated NEU3 likely spans the lipid bilayer with a portion of C-terminus exposed to cytosol and the catalytic region facing the extracellular space (By similarity). Expressed in heart, brain and cerebral cortex. Palmitoylated; may regulate intracellular trafficking and anchorage to plasma membrane and endomembranes. Belongs to the glycosyl hydrolase 33 family.