PAI-1: An Integrator of Cell Signaling and Migration
Figure 5
PAI-1-VN interactions disrupt the receptor binding events and regulate cell adhesion. On a VN matrix, cells are attached through binding of uPAR and integrins to VN, and these interactions are supported by uPA in complex with uPAR (step 1). Secreted PAI-1 will bind to and inactivate uPA, consequently decrease the affinities of uPAR and integrins for VN, and initiate cell detachment and subsequent LRP1-mediated endocytic clearance of those quaternary complexes (step 2). Excess extracellular PAI-1 can now bind to the unoccupied SMB domain in VN and prevent reattachment of uPAR to that site as well as integrins to the adjacent RGD sequence (step 3). Once recycled integrins are engaging with unoccupied VN, PAI-1 is unable to displace these integrins competitively (step 4). Those integrins are then available for complex formation with recycled uPAR in the presence of uPA (step 5; see also step 1). In a similar manner, VN binding to PAI-1 inhibits the interaction of PAI-1 with LRP1 and, as a consequence, prevents Jak/Stat1-mediated migration (step 6). Collectively, this may promote cell movement away from a PAI-1-abundant VN-rich matrix onto an alternative substrate that cannot be saturated by PAI-1 and where PAI-1 only regulates cell attachment through interaction with uPA/uPAR complexes.
