Signaling through JAM-1 and alphavbeta3 is required for the angiogenic action of bFGF: dissociation of the JAM-1 and alphavbeta3 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 alphavbeta3 is specific to basic fibroblast growth factor (bFGF)-induced angiogenesis. Here we show that junctional adhesion molecule 1/A (JAM-1/A) and alphavbeta3 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 angiogenesis. 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-1/ alphavbeta3 complex, allowing for signaling through JAM-1 and alphavbeta3. In addition, blockage of either JAM-1 or alphavbeta3 inhibits bFGF-induced MAP kinase activation. Thus, our results suggest that signaling through JAM-1 and alphavbeta3 is necessary for bFGF-induced angiogenesis.
Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
Meghna U
MU
Naik
Shaker A
SA
Mousa
Charles A
CA
Parkos
Ulhas P
UP
Naik
D000482:Allantois / Q000098:blood supply; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D015815:Cell Adhesion Molecules; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology*; D011956:Receptors, Cell Surface; D014471:Umbilical Veins / Q000166:cytology
D015815:Cell Adhesion Molecules; C407243:F11R protein, human; D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D016222:Fibroblast Growth Factor 2