Integrin cleavage regulates bidirectional signalling in vascular smooth muscle cells.
Integrins link the cytoskeleton to the extracellular matrix, providing outside-in/inside-out signalling essential for vascular smooth muscle cell (VSMC) migration in atherosclerosis. The integrin av subunit is synthesised from its precursor via furin-dependent endoproteolytic cleavage. Furin is a proprotein convertase (PC) highly expressed in VSMCs and in human atherosclerotic lesions. Inhibition of av processing inhibits binding to vitronectin and migration. However, the precise role of furin-dependent av cleavage on integrin bidirectional signalling and subsequent VSMC functions is unknown. Our present study demonstrates that the furin-like PC inhibitor decanoyl-RVKR-chloromethylketone (dec-CMK) inhibited av cleavage. This reduced vitronectin-induced (outside-in) focal adhesion kinase (FAK)- and paxillin-phosphorylation, and VSMC motility. Inside-out-stimulated, integrin- mediated VSMC adhesion/migration relied on integrin-adaptor protein activation following protein kinase C (PKC) and ERK1/2 phosphorylation. In contrast to outside-in signalling, PKC-dependent phosphorylation of FAK and paxillin was unaffected by the status of integrin cleavage. Still, cytoskeleton and focal adhesion site rearrangements were modulated by the inhibition of furin-dependent integrin cleavage, thereby lessening inside-out dependent migration. Hence, we find that integrin bidirectional signalling is critically controlled by furin. Furin- dependent integrin processing modulates rapid adaptive integrin/cytoskeleton changes, essential to VSMC motility, which represents a crucial component in atherosclerosis and restenosis.
Kappert
Kai
K
Department of Medicine/ Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany.
Furundzija
Vesna
V
Fritzsche
Jan
J
Margeta
Christian
C
Krüger
Janine
J
Meyborg
Heike
H
Fleck
Eckart
E
Stawowy
Philipp
P
D000818:Animals; D050197:Atherosclerosis / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D003599:Cytoskeleton; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D045683:Furin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D016023:Integrins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
D016023:Integrins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D045683:Furin