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N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling
U Cavallaro1, J Niedermeyer, M Fuxa
1Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Abstract:
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.
Insights
Neural cell-adhesion molecule (N-CAM) loss promotes tumour metastasis. N-CAM activates fibroblast-growth-factor receptor-4 (FGFR-4) signaling, enhancing pancreatic cancer cell adhesion and potentially preventing cancer spread.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Loss of neural cell-adhesion molecule (N-CAM) expression is linked to tumor metastasis.
- Understanding the molecular mechanisms behind N-CAM's role in cancer progression is crucial.
Purpose of the Study:
- To investigate how N-CAM influences pancreatic tumor beta-cell behavior, specifically neurite outgrowth and matrix adhesion.
- To elucidate the signaling pathways involved in N-CAM-mediated cell adhesion.
Main Methods:
- Analysis of N-CAM's role in assembling a signaling complex including N-cadherin, FGFR-4, PLC-gamma, FRS2, pp60(c-src), cortactin, and GAP-43.
- Utilizing dominant-negative FGFR-4, FGFR signaling inhibitors, and anti-beta(1)-integrin antibodies to assess effects on matrix adhesion.
- Investigating the role of FGF ligands in N-CAM-mediated processes.
Main Results:
- N-CAM modulates neurite outgrowth and matrix adhesion in pancreatic tumor beta-cells.
- N-CAM assembles a signaling complex involving FGFR-4, N-cadherin, and other key proteins.
- FGFR signaling inhibition and anti-beta(1)-integrin antibodies reduce N-CAM-induced matrix adhesion.
- FGF ligands promote matrix adhesion but not neurite outgrowth, suggesting distinct roles.
Conclusions:
- N-CAM stimulates beta1-integrin-mediated cell-matrix adhesion through activation of FGFR signaling.
- This mechanism presents a potential strategy for inhibiting the dissemination of metastatic tumor cells.