Gangliosides Inhibit Urokinase-Type Plasminogen Activator (uPA)-Dependent Squamous Carcinoma Cell Migration by Preventing uPA Receptor/α5β1 Integrin/Epidermal Growth Factor Receptor Interactions

The interaction of the urokinase-type plasminogen activator (uPA) receptor (uPAR) with integrins plays a critical role in the regulation of cell adhesion and migration. However, the molecular events underlying the modulation of the interaction of uPAR and integrin are poorly understood. Gangliosides are thought to regulate epithelial cell adhesion and migration by inhibiting α5β1 integrin and epidermal growth factor receptor (EGFR) signaling. We report here that increases in the expression of ganglioside NeuAcα2→3Galβ1→3GalNAcβ1→4(NeuAcα2→8NeuAcα2→3)Galβ1→4Glcβ1-Cer (GT1b) or NeuAcα2→3Galβ1→4Glcβ1-Cer (GM3) inhibit uPA-dependent cell migration by preventing the association of uPAR with α5β1 integrin or uPAR/α5β1 integrin with the EGFR, respectively. As a result, uPA-dependent focal adhesion kinase (FAK) and integrin-mediated EGFR signaling are suppressed. Both gangliosides inhibit uPAR signaling-stimulated migration; however, GM3 inhibits uPA-induced EGFR phosphorylation by blocking the crosstalk between integrin and EGFR, whereas GT1b suppresses both uPA-induced FAK and EGFR activation by preventing the activation of integrin α5β1.