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N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling

Nature Cell Biology volume 3, pages 650–657 (2001)Cite this article

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 β-cells from pancreatic tumours by assembling a fibroblast-growth-factor receptor-4 (FGFR-4) signalling complex, which consists of N-cadherin, FGFR-4, phospholipase Cγ (PLC-γ), the adaptor protein FRS2, pp60c-src, cortactin and growth-associated protein-43 (GAP-43). Dominant-negative FGFR-4, inhibitors of FGFR signalling and anti-β1-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 β1-integrin-mediated cell–matrix adhesion by activating FGFR signalling. This is a potential mechanism for preventing the dissemination of metastatic tumour cells.

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Figure 1: Dramatic tissue disaggregation (A) and impairment of cell–matrix adhesion in N-CAM-deficient tumour β-cells (B).
Figure 2: N-CAM-dependent neurite outgrowth in tumour β-cells.
Figure 3: N-CAM modulates neurite outgrowth and cell–matrix adhesion.
Figure 4: N-CAM associates with FGFR-4, PLC-γ, FRS2, pp60c-src and cortactin.
Figure 5: N-CAM associates with FGFR-4 in L cells.
Figure 6: Inhibition of N-CAM-dependent neurite outgrowth and matrix adhesion.
Figure 7: N-CAM-dependent assembly of signalling complexes.
Figure 8: Modulation of cell–matrix adhesion and of p42/44 MAPK activation by FGFs.

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Acknowledgements

We thank P. Wilgenbus for technical support, K. Paiha and P. Steinlein for confocal microscopy, K. Alitalo, A. Ullrich, H. Semb, A. Vecchi and Yoshimoto Pharmaceuticals for cells and reagents, and E. Wagner, B. Dickson and M. Cotten for critical comments on the manuscript. This work was supported by Boehringer Ingelheim, by the Austrian Industrial Research Promotion Fund, and the Austrian Science Foundation. U.C. is enrolled in the Doctoral Programme in Experimental Pathology of the University of Florence. J.N. was in part supported by a postdoctoral fellowship from the Deutsche Akademische Austauschdienst.

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  1. Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, Vienna, A-1030, Austria

    Ugo Cavallaro, Joachim Niedermeyer, Martin Fuxa & Gerhard Christofori

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Correspondence to Gerhard Christofori.

Supplementary information

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Figure S1 Cell–cell adhesion is not significantly impaired in N-CAM-deficient tumour β-cells. (PDF 283 kb)

Figure S2 N-CAM-associated tyrosine phophorylation.

Figure S3 Significance of the N-CAM/FGFR-4/N-cadherin signalling complex.

Figure S4 Activation of p42/44 MAPK.

Figure S5 A model of N-CAM-mediated signal transduction in tumour β-cells.

Cell–cell adhesion is not significantly impaired in N-CAM-deficient tumour β-cells.

Figure S2 N-CAM-associated tyrosine phophorylation.

Figure S3 Significance of the N-CAM/FGFR-4/N-cadherin signalling complex.

Figure S4 Activation of p42/44 MAPK.

Figure S5 A model of N-CAM-mediated signal transduction in tumour β-cells.

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Cavallaro, U., Niedermeyer, J., Fuxa, M. et al. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol 3, 650–657 (2001). https://doi.org/10.1038/35083041

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