PAI-1: An Integrator of Cell Signaling and Migration

Figure 4

PAI-1 modulates migration through cell surface receptors. PAI-1 binding to LRP1, in a non-uPA/uPAR-dependent manner, triggers Jak/Stat1 signaling events that culminate in enhanced cell migration (left). It is unclear whether this process requires PAI-1 interaction with the ECM. PAI-1 binding to uPA/uPAR results in the internalization of the PAI-1/uPA/uPAR complexes in an LRP1-dependent manner (middle). PAI-1 binding to uPA/uPAR can also trigger the detachment of cell surface integrins from their ECM ligands and subsequent internalization in an LRP1-uPA/uPAR-dependent manner. In each case, receptors (integrin, uPAR, LRP1) recycled back to the cell surface, while uPA and PAI-1 are degraded. PAI-1, through its ability to titer active plasmin, may also promote syndecan-1-dependent migration on unprocessed laminin-332 by preventing the cleavage of the syndecan-binding site LG4/5 (right). Additionally, inhibition of plasmin activation by PAI-1 facilitates migration on unprocessed laminin-332 by reducing the shedding of syndecan-1 from the cell surface. As the proteolytic environment matures and PAI-1 levels decrease, integrins α3β1 and α6β4 (not shown) engage the proteolytically-cleaved or processed form of laminin-332 facilitating construction of hemidesmosomes.