N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling.
Loss of expression of neural cell-adhesion molecule (N-CAM) is implicated in the progression of tumour metastasis. Here we show that N-CAM modulates neurite outgrowth and matrix adhesion of beta-cells from pancreatic tumours by assembling a fibroblast-growth-factor receptor-4 (FGFR-4) signalling complex, which consists of N-cadherin, FGFR-4, phospholipase C gamma (PLC-gamma), the adaptor protein FRS2, pp60(c-src), cortactin and growth-associated protein-43 (GAP-43). Dominant-negative FGFR-4, inhibitors of FGFR signalling and anti-beta(1)-integrin antibodies repress matrix adhesion induced by N-CAM. FGF ligands can replace N-CAM in promoting matrix adhesion but not neurite outgrowth. The results indicate that N-CAM stimulates beta1-integrin-mediated cell-matrix adhesion by activating FGFR signalling. This is a potential mechanism for preventing the dissemination of metastatic tumour cells.