Abstract : The intracellular signaling events that cause 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 stability. Association of FGFR with N-cadherin was mediated by the first two Ig-like domains of FGFR. These results suggest that protection of the FGFR from ligand-induced downregulation by N-cadherin enhances receptor signaling and provides a mechanism by which tumor cells can acquire metastatic properties