Abstract
Integrins govern cellular adhesion and transmit signals leading to
activation of intracellular signaling pathways aimed to prevent apoptosis.
Herein we report that attachment of oligodendrocytes (OLs) to fibronectin via
α
v
β
3
integrin receptors rendered the cells
more resistant to apoptosis than the cells attached to laminin via
α
6
β
1
integrins. Investigation of molecular
mechanisms involved in α
v
β
3
integrin-mediated
cell survival revealed that ligation of the integrin with fibronectin results
in higher expression of activated Lyn kinase. Both in OLs and in the mouse
brain, Lyn selectively associates with α
v
β
3
integrin, not with α
v
β
5
integrin, leading to
suppression of acid sphingomyelinase activity and preventing ceramide-mediated
apoptosis. In OLs, knockdown of Lyn with small interfering RNA resulted in OL
apoptosis with concomitant accumulation of C
16
-ceramide due to
activation of acid sphingomyelinase (ASMase) and sphingomyelin hydrolysis.
Knocking down ASMase partially protected OLs from apoptosis. In the brain,
ischemia/reperfusion (IR) triggered rearrangements in the
α
v
β
3
integrin-Lyn kinase complex leading to
disruption of Lyn kinase-mediated suppression of ASMase activity. Thus,
co-immunoprecipitation studies revealed an increased association of
α
v
β
3
integrin-Lyn kinase complex with
ionotropic glutamate receptor subunits, GluR2 and GluR4, after cerebral IR.
Sphingolipid analysis of the brain demonstrated significant accumulation of
ceramide and sphingomyelin hydrolysis. The data suggest a novel mechanism for
regulation of ASMase activity during cell adhesion in which Lyn acts as a key
upstream kinase that may play a critical role in cerebral IR injury.
