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:11298736, PubMed:15847605, PubMed:10861246, PubMed:20511247, PubMed:28646141, PubMed:10405317, PubMed:12011038). 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 (PubMed:17334392, PubMed:25922362). Desialylates EGFR and activates downstream signaling in proliferating cells (PubMed:25922362). Contributes to clathrin-mediated endocytosis by regulating sorting of endocytosed receptors to early and recycling endosomes (PubMed:26251452). 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 4.5-6.5. Optimum temperature is 20 degrees Celsius. Interacts with CAV1; this interaction enhances NEU3 sialidase activity within caveola (PubMed:12011038). Interacts with EGFR; this interaction mediates desialylation of EGFR and enhances downstream signaling (PubMed:17334392). Associates with the external leaflet of the plasma membrane (By similarity). S-acylated NEU3 likely spans the lipid bilayer with a portion of C-terminus exposed to the cytosol and the catalytic region facing the extracellular space (PubMed:28646141). Highly expressed in skeletal muscle, testis, adrenal gland and thymus, followed by pancreas, liver, heart and thymus. Weakly expressed in kidney, placenta, brain and lung. Palmitoylated; may regulate intracellular trafficking and anchorage to plasma membrane and endomembranes. Belongs to the glycosyl hydrolase 33 family. Extended N-terminus.