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

Alexander Kapustin, Victoria Stepanova, Natalia Aniol, Douglas B. Cines, Alexei Poliakov, Serge Yarovoi, Tatiana Lebedeva, Robin Wait, Grigory Ryzhakov, Yelena Parfyonova, Yaroslav Gursky, Hiromi Yanagisawa, Mikhail Minashkin, Robert Beabealashvilli, Alexander Vorotnikov, Alex Bobik, Vsevolod Tkachuk

Research output: Contribution to journalArticle

23 Scopus citations

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 (Ca 2+-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.

Original languageEnglish (US)
Pages (from-to)491-503
Number of pages13
JournalBiochemical Journal
Volume443
Issue number2
DOIs
StatePublished - Apr 15 2012

Keywords

  • Fibroblast
  • Fibulin-5
  • Migration
  • Urokinase
  • Vascular pathology

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kapustin, A., Stepanova, V., Aniol, N., Cines, D. B., Poliakov, A., Yarovoi, S., Lebedeva, T., Wait, R., Ryzhakov, G., Parfyonova, Y., Gursky, Y., Yanagisawa, H., Minashkin, M., Beabealashvilli, R., Vorotnikov, A., Bobik, A., & Tkachuk, V. (2012). Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated β1-integrin-dependent cell migration. Biochemical Journal, 443(2), 491-503. https://doi.org/10.1042/BJ20110348