The junctions of the endothelium consist a major barrier for the extravasation of leukocytes during inflammation as well as for the blood-borne metastasis of tumor cells. We have previously identified junctional adhesion molecule-C (JAM-C), and could demonstrate that JAM-C is expressed at the interendothelial junctions and serves as a counter-receptor for neutrophil Mac-1, mediating the transendothelial migration of inflammatory cells in vitro and in vivo. We have recently found that JAM-C regulates endothelial paracellular permeability. In contrast to other transmembrane molecules of the endothelial junctions that act as gatekeepers, JAM-C was identified as the first molecule to mediate an increase in paracellular permeability. JAM-C regulates the activity of the small GTPase Rap1 and thereby the integrity of adherens junctions. Moreover, JAM-C in endothelial cells facilitates stress fiber formation. JAM-C inhibition in vivo blocks the VEGF or histamine induced permeability as well as hypoxia-driven retina angiogenesis. Our current investigations include: a) The importance of JAM-C in leukocyte recruitment in vivo is tested with the use of JAM-C -/- mice, by using several inflammation models, such as chemical peritonitis and lung inflammation. b) We found that melanoma cells express JAM-C. The homophilic interaction of JAM-C, i.e. the interaction between JAM-C on melanoma cells and JAM-C on the endothelium, was found to mediate the migration of melanoma cells through the endothelium in vitro and thereby melanoma metastasis in vivo.
