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.
Cavallaro
U
U
Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Niedermeyer
J
J
Fuxa
M
M
Christofori
G
G
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism*; D019012:Integrin beta1 / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control; D019006:Neural Cell Adhesion Molecules / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000556:secondary; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000502:physiology
D019012:Integrin beta1; D008024:Ligands; D019006:Neural Cell Adhesion Molecules; D017468:Receptors, Fibroblast Growth Factor; C496372:Fgfr4 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4