| First Author | Kapustin A | Year | 2012 |
| Journal | Biochem J | Volume | 443 |
| Issue | 2 | Pages | 491-503 |
| PubMed ID | 22280367 | Mgi Jnum | J:328822 |
| Mgi Id | MGI:6855025 | Doi | 10.1042/BJ20110348 |
| Citation | Kapustin A, et al. (2012) Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated beta1-integrin-dependent cell migration. Biochem J 443(2):491-503 |
| abstractText | uPA (urokinase-type plasminogen activator) stimulates cell migration through multiple pathways, including formation of plasmin and extracellular metalloproteinases, and binding to the uPAR (uPA receptor; also known as CD87), integrins and LRP1 (low-density lipoprotein receptor-related protein 1) which activate intracellular signalling pathways. In the present paper we report that uPA-mediated cell migration requires an interaction with fibulin-5. uPA stimulates migration of wild-type MEFs (mouse embryonic fibroblasts) (Fbln5+/+ MEFs), but has no effect on fibulin-5-deficient (Fbln5-/-) MEFs. Migration of MEFs in response to uPA requires an interaction of fibulin-5 with integrins, as MEFs expressing a mutant fibulin-5 incapable of binding integrins (Fbln(RGE/RGE) MEFs) do not migrate in response to uPA. Moreover, a blocking anti-(human beta1-integrin) antibody inhibited the migration of PASMCs (pulmonary arterial smooth muscle cells) in response to uPA. Binding of uPA to fibulin-5 generates plasmin, which excises the integrin-binding N-terminal cbEGF (Ca2+-binding epidermal growth factor)-like domain, leading to loss of beta1-integrin binding. We suggest that uPA promotes cell migration by binding to fibulin-5, initiating its cleavage by plasmin, which leads to its dissociation from beta1-integrin and thereby unblocks the capacity of integrin to facilitate cell motility. |
