Fig. 4. Model for Modulation of Integrin Signaling by uPA/R. A metastasizing cell encounters a 3D ECM barrier, leading to multivalent integrin clustering. This activates a signal transduction pathway leading to transcriptional activation of the uPA promoter, secretion of the proteinase, and interaction with surface-associated uPAR. Membrane re-distribution of ligand-bound uPAR and integrins leads to lateral association of uPAR with α3β1 integrin, potentially altering the magnitude and duration of integrin signaling. Our studies indicate that highly metastatic OSCC may lose the capacity for matrix-regulated proteinase expression, resulting in consititutively high pericellular proteolysis and enhanced invasive capacity.