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Integrin cleavage regulates bidirectional signalling in vascular smooth muscle cells
Kai Kappert1, Vesna Furundzija, Jan Fritzsche
1Department of Medicine/ Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany.
Thrombosis and Haemostasis
|January 16, 2010
Summary
Furin-dependent integrin processing is crucial for vascular smooth muscle cell migration in atherosclerosis. Inhibiting this process affects cell signaling and movement, offering potential therapeutic targets.
Area of Science:
- Cell Biology
- Biochemistry
- Cardiovascular Research
Background:
- Integrins mediate cell-extracellular matrix interactions, crucial for vascular smooth muscle cell (VSMC) migration in atherosclerosis.
- Integrin alpha-v (av) subunit processing by furin, a proprotein convertase (PC), is vital for VSMC function.
- The exact role of furin-dependent av cleavage in integrin bidirectional signaling and VSMC functions remains unclear.
Purpose of the Study:
- To investigate the precise role of furin-dependent av cleavage in integrin bidirectional signaling.
- To determine the impact of inhibiting furin-dependent av cleavage on VSMC functions, including migration and adhesion.
- To elucidate how furin influences integrin-mediated outside-in and inside-out signaling pathways.
Main Methods:
- Utilized decanoyl-RVKR-chloromethylketone (dec-CMK), a furin-like PC inhibitor, to block av cleavage.
- Assessed vitronectin-induced (outside-in) signaling by measuring focal adhesion kinase (FAK) and paxillin phosphorylation.
- Evaluated inside-out signaling by examining protein kinase C (PKC) and ERK1/2 phosphorylation and their downstream effects on VSMC adhesion and migration.
Main Results:
- Dec-CMK treatment inhibited av cleavage, reducing vitronectin-induced FAK and paxillin phosphorylation and VSMC motility.
- Inside-out signaling, dependent on PKC and ERK1/2, was less affected by integrin cleavage status regarding FAK/paxillin phosphorylation.
- Inhibition of furin-dependent integrin cleavage modulated cytoskeleton and focal adhesion rearrangements, impairing inside-out dependent migration.
Conclusions:
- Integrin bidirectional signaling is critically regulated by furin.
- Furin-dependent integrin processing impacts rapid, adaptive changes in integrin-cytoskeleton interactions essential for VSMC motility.
- Targeting furin-mediated integrin processing may offer a novel strategy for treating atherosclerosis and restenosis.
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