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 (FblnRGE/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.
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Research Article|
March 27 2012
Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated β1-integrin-dependent cell migration
Alexander Kapustin;
*Faculty of Fundamental Medicine, MV Lomonosov Moscow State University, Moscow 119192, Russia
2To whom correspondence should be addressed at the present address: Department of Cardiology, The James Black Centre, Kings College London, 125 Coldharbour Lane, London SE5 9NU, U.K. (email alexander.kapustin@kcl.ac.uk).
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Victoria Stepanova;
Victoria Stepanova
1
†Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
‡Russian Cardiology Research Center, Moscow 121552, Russia
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Natalia Aniol;
Natalia Aniol
*Faculty of Fundamental Medicine, MV Lomonosov Moscow State University, Moscow 119192, Russia
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Douglas B. Cines;
Douglas B. Cines
†Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Alexei Poliakov;
Alexei Poliakov
§The National Institute for Medical Research, London NW7 1AA, U.K.
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Serge Yarovoi;
Serge Yarovoi
†Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Tatiana Lebedeva;
Tatiana Lebedeva
†Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Robin Wait;
Robin Wait
∥Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London W6 8LH, U.K.
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Grigory Ryzhakov;
Grigory Ryzhakov
‡Russian Cardiology Research Center, Moscow 121552, Russia
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Yelena Parfyonova;
Yelena Parfyonova
‡Russian Cardiology Research Center, Moscow 121552, Russia
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Yaroslav Gursky;
Yaroslav Gursky
‡Russian Cardiology Research Center, Moscow 121552, Russia
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Hiromi Yanagisawa;
Hiromi Yanagisawa
¶Department of Molecular Biology, University of Texas Southwestern Medical Center, Texas 75390-9148, U.S.A.
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Mikhail Minashkin;
Mikhail Minashkin
‡Russian Cardiology Research Center, Moscow 121552, Russia
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Robert Beabealashvilli;
Robert Beabealashvilli
‡Russian Cardiology Research Center, Moscow 121552, Russia
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Alexander Vorotnikov;
Alexander Vorotnikov
*Faculty of Fundamental Medicine, MV Lomonosov Moscow State University, Moscow 119192, Russia
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Alex Bobik;
Alex Bobik
**Baker-IDI Heart and Diabetes Institute, Alfred Hospital, Melbourne 3004, Australia
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Vsevolod Tkachuk
Vsevolod Tkachuk
*Faculty of Fundamental Medicine, MV Lomonosov Moscow State University, Moscow 119192, Russia
‡Russian Cardiology Research Center, Moscow 121552, Russia
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Publisher: Portland Press Ltd
Received:
March 01 2011
Revision Received:
December 23 2011
Accepted:
January 26 2012
Accepted Manuscript online:
January 26 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (2): 491–503.
Article history
Received:
March 01 2011
Revision Received:
December 23 2011
Accepted:
January 26 2012
Accepted Manuscript online:
January 26 2012
Citation
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; Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated β1-integrin-dependent cell migration. Biochem J 15 April 2012; 443 (2): 491–503. doi: https://doi.org/10.1042/BJ20110348
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