We have found previously that
human plasma-membrane-associated sialidase (NEU3), a key
glycosidase for
ganglioside degradation, was markedly up-regulated in human
colon cancers, with an involvement in suppression of apoptosis. To elucidate the molecular mechanisms underlying increased NEU3 expression, in the present study we investigated its role in cell adhesion of human
colon cancer cells. DLD-1 cells transfected with NEU3 exhibited increased adhesion to laminins and consequent cell proliferation, but decreased cell adhesion to
fibronectin and
collagens I and IV, compared with control cells. When triggered by laminins, NEU3 clearly stimulated phosphorylation of FAK (
focal adhesion kinase) and ERK (
extracellular-signal-regulated kinase), whereas there was no activation on
fibronectin. NEU3 markedly enhanced
tyrosine phosphorylation of
integrin beta4 with recruitment of Shc and Grb-2 only on
laminin-5, and NEU3 was co-immunoprecipitated by an anti-(integrin beta4) antibody, suggesting that association of NEU3 with
integrin beta4 might facilitate promotion of the
integrin-derived signalling on
laminin-5. In addition, the promotion of phosphorylation of
integrin beta1 and ILK (
integrin-linked kinase) was also observed on laminins. G(M3) depletion as the result of NEU3 overexpression, assessed by TLC, appeared to be one of the causes of the increased adhesion on laminins and, in contrast, of the decreased adhesion on
fibronectin - NEU3 probably having bimodal effects. These results indicate that NEU3 differentially regulates cell proliferation through
integrin-mediated signalling depending on the extracellular matrix and, on laminins, NEU3 did indeed activate molecules often up-regulated in
carcinogenesis, which may cause an acceleration of the malignant phenotype in
cancer cells.