title: Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated β1-integrin-dependent cell migration.
abstract: 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.
authors.affiliation: Faculty of Fundamental Medicine, MV Lomonosov Moscow State University, Moscow, Russia. alexander.kapustin@kcl.ac.uk
authors.forename: Alexander
authors.initials: A
authors.lastname: Kapustin
authors.forename: Victoria
authors.initials: V
authors.lastname: Stepanova
authors.forename: Natalia
authors.initials: N
authors.lastname: Aniol
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Alexei
authors.initials: A
authors.lastname: Poliakov
authors.forename: Serge
authors.initials: S
authors.lastname: Yarovoi
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lebedeva
authors.forename: Robin
authors.initials: R
authors.lastname: Wait
authors.forename: Grigory
authors.initials: G
authors.lastname: Ryzhakov
authors.forename: Yelena
authors.initials: Y
authors.lastname: Parfyonova
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Gursky
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanagisawa
authors.forename: Mikhail
authors.initials: M
authors.lastname: Minashkin
authors.forename: Robert
authors.initials: R
authors.lastname: Beabealashvilli
authors.forename: Alexander
authors.initials: A
authors.lastname: Vorotnikov
authors.forename: Alex
authors.initials: A
authors.lastname: Bobik
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Tkachuk
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; C120769:Fbln5 protein, mouse; D011994:Recombinant Proteins; D014568:Urokinase-Type Plasminogen Activator