A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor.
The intracellular signaling events causing tumor cells to become metastatic are not well understood. N-cadherin and FGF-2 synergistically increase migration, invasion, and secretion of extracellular proteases in breast tumor cells. Here, we define a metastatic signaling cascade activated by N-cadherin and FGF-2. In the presence of N-cadherin, FGF-2 caused sustained activation of the MAPK-ERK pathway, leading to MMP-9 gene transcription and cellular invasion. N-cadherin prevented the FGF receptor (FGFR) from undergoing ligand-induced internalization, resulting in increased FGFR-1 stability. Association of FGFR-1 with N-cadherin was mediated by the first two Ig-like domains of FGFR-1. These results suggest that protection of the FGFR-1 from ligand-induced downregulation by N-cadherin enhances receptor signaling and provides a mechanism by which tumor cells can acquire metastatic properties.
Suyama
Kimita
K
Derald H Ruttenberg Cancer Center, The Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA.
Shapiro
Irina
I
Guttman
Mitchell
M
Hazan
Rachel B
RB
D000818:Animals; D015820:Cadherins / Q000502:physiology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D015820:Cadherins; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020780:Matrix Metalloproteinase 9