Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated β1-integrin-dependent cell migration

• Published in: Biochemical journal Vol. 443; no. 2; p. 491
• Main Authors: Kapustin, Alexander, Stepanova, Victoria, Aniol, Natalia, Cines, Douglas B, Poliakov, Alexei, Yarovoi, Serge, Lebedeva, Tatiana, Wait, Robin, Ryzhakov, Grigory, Parfyonova, Yelena, Gursky, Yaroslav, Yanagisawa, Hiromi, Minashkin, Mikhail, Beabealashvilli, Robert, Vorotnikov, Alexander, Bobik, Alex, Tkachuk, Vsevolod
• Format: Journal Article
• Language: English
• Published: England 15-04-2012
• Subjects: Animals; Cell Movement; Cells, Cultured; Extracellular Matrix Proteins - deficiency; Extracellular Matrix Proteins - metabolism; Humans; Mice; Mice, Knockout; Protein Binding; Recombinant Proteins - metabolism; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism
• ISSN: 1470-8728
• DOI: 10.1042/bj20110348

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 β1-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 β1-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 β1-integrin and thereby unblocks the capacity of integrin to facilitate cell motility.