Signaling through JAM-1 and ανβ3 is required for the angiogenic action of bFGF:: dissociation of the JAM-1 and ανβ3 complex

Growth factor-induced neovascularization has received a great deal of attention because it is fundamental to the growth and metastasis of solid tumors. This multistep process requires extensive signaling through growth factor receptors and integrins. Among the integrins involved in this process, integrin alpha(v)beta(3) is specific to basic fibroblast growth factor (bFGF)induced angiogenesis. Here we show that junctional adhesion molecule 1/A (JAM-1/A) and alpha(v)beta(3) form a complex in the absence of bFGF. JAM-1, which is normally localized at the cell-cell junctions of quiescent endothelial cells, redistributes to the cell surface on bFGF treatment. Blockage of the extracellular domain of JAM-1 inhibits bFGF-Induced endothelial cell morphology, proliferation, and angio-genesis. Additionally, mutation in the JAM-1 cytoplasmic domain blocks bFGF-induced mitogen-activated protein (MAP) kinase activation and ablates its ability to induce endothelial cell tube formation, suggesting that signaling through JAM-1 is key to bFGF-induced signaling. immunoprecipitation analysis suggests that bFGF signaling dissociates the JAM-1alpha(v)beta(3) complex, allowing for signaling through JAM-1 and of alpha(v)beta(3). In addition, blockage of either JAM-1 or alpha(v)beta(3) inhibits bFGF-induced MAP kinase activation. Thus, our results suggest that signaling through JAM-1 and alpha(v)beta(3) is necessary for bFGF-induced angiogenesis.