Src-dependent, neutrophil-mediated vascular hyperpermeability and beta-catenin modification.
The hyperpermeability response of microvessels in inflammation involves complex signaling reactions and structural modifications in the endothelium. Our goal was to determine the role of Src-family kinases (Src) in neutrophil-mediated venular hyperpermeability and possible interactions between Src and endothelial barrier components. We found that inhibition of Src abolished the increases in albumin permeability caused by C5a-activated neutrophils in intact, perfused coronary venules, as well as in cultured endothelial monolayers. Activated neutrophils increased Src phosphorylation at Tyr416, which is located in the catalytic domain, and decreased phosphorylation at Tyr527 near the carboxyl terminus, events consistent with reports that phosphorylating and transforming activities of Src are upregulated by Tyr416 phosphorylation and negatively regulated by Tyr527 phosphorylation. Furthermore, neutrophil stimulation resulted in association of Src with the endothelial junction protein beta-catenin and beta-catenin tyrosine phosphorylation. These phenomena were abolished by blockage of Src activity. Taken together, our studies link for the first time neutrophil-induced hyperpermeability to a pathway involving Src kinase activation, Src/beta-catenin association, and beta-catenin tyrosine phosphorylation in the microvascular endothelium.
Tinsley
John H
JH
Department of Surgery, Cardiovascular Research Institute, Texas A&M University System Health Science Center, Temple, Texas 76504, USA. jht@tamu.edu
Ustinova
Elena E
EE
Xu
Wenjuan
W
Yuan
Sarah Y
SY
D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D009504:Neutrophils / Q000502:physiology*; D010766:Phosphorylation; D013552:Swine; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin; D019061:src-Family Kinases / Q000502:physiology*
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D014443:Tyrosine; D019061:src-Family Kinases