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Department of Immunology, The Scripps Research Institute, La Jolla, California 92037
Previously, we reported that urokinase-type plasminogen activator (uPA) plays a pivotal role in extracellular matrix dissolution by malignant melanoma cells. Here, we demonstrate that a highly metastatic melanoma cell line (M24met) that secretes uPA expresses high levels of the uPA receptor (uPAR), 2.4 x 106 binding sites/cell with a KD of 5.67 x 10-10 M. The receptor was identified as a 55,000–60,000 kDa cell surface protein. Although M24met cells secrete uPA, they are unable to efficiently utilize this enzyme for invasion, unless it is bound to its receptor. This contention is based on the finding that an antibody against uPAR (monoclonal antibody 3936) inhibited invasion of M24met cells through a reconstituted basement membrane (Matrigel) up to 33%, while a reduction of uPA catalytic activity by its plasminogen activator inhibitor-2 resulted in 46% inhibition of invasion. Furthermore, uPAR is involved in signal transduction events in M24met cells, since both uPA and its amino-terminal fragment stimulated the migration of melanoma cells toward Matrigel, resulting in maximal increases of 32 and 72%, respectively. Our results indicate that both uPA and uPAR are involved in melanoma metastasis and that uPAR contributes to at least two important steps in this process, matrix dissolution and migration.
1 Data presented in this publication were obtained by A.S. as part of his doctoral thesis to be submitted to the Faculty of Biology at the University of Hamburg. This is The Scripps Research Institute manuscript 8370-IMM.
2 Recipient of a fellowship from the Studienstiftung des Deutschen Volkes.
3 To whom requests for reprints should be addressed, at Department of Immunology, The Scripps Research Institute, 10666 N. Torrey Pines Road, La Jolla, CA 92037.
Received 12/13/93. Accepted 4/ 5/94.
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