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1 Division of Pulmonary and
Critical Care Medicine, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21224;
3 Richard Roudebush Veterans
Affairs Medical Center,
Inflammatory
diseases of the lung are characterized by increases in
vascular permeability and enhanced leukocyte infiltration, reflecting
compromise of the endothelial cell (EC) barrier. We examined potential
molecular mechanisms that underlie these alterations and assessed the
effects of diperoxovanadate (DPV), a potent tyrosine kinase activator
and phosphatase inhibitor, on EC contractile events. Confocal
immunofluorescent microscopy confirmed dramatic increases in
stress-fiber formation and colocalization of EC myosin light chain
(MLC) kinase (MLCK) with the actin cytoskeleton, findings consistent
with activation of the endothelial contractile apparatus. DPV produced
significant time-dependent increases in MLC phosphorylation that were
significantly attenuated but not abolished by EC MLCK inhibition with
KT-5926. Pretreatment with the Rho GTPase-inhibitory C3 exotoxin completely abolished
DPV-induced MLC phosphorylation, consistent with Rho-mediated MLC
phosphatase inhibition and novel regulation of EC MLCK activity.
Immunoprecipitation of EC MLCK after DPV challenge revealed dramatic
time-dependent tyrosine phosphorylation of the kinase in association
with increased MLCK activity and a stable association of MLCK with the
p85 actin-binding protein cortactin and
p60src. Translocation of
immunoreactive cortactin from the cytosol to the cytoskeleton was noted
after DPV in concert with cortactin tyrosine phosphorylation. These
studies indicate that DPV activates the endothelial contractile
apparatus in a Rho GTPase-dependent fashion and suggests that
p60src-induced tyrosine
phosphorylation of MLCK and cortactin may be important features of
contractile complex assembly.
Src kinases; myosin phosphorylation; endothelial cell contraction; permeability
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