Association of FAK activation with lentivirus-induced disruption of blood-brain barrier tight junction-associated ZO-1 protein organization.
Expression of tight junction proteins between brain microvascular endothelial cells (BMECs) of the blood-brain barrier (BBB) is lost during development of human immunodeficiency virus (HIV) encephalitis (HIVE). Although many studies have focused on the strains of virus that induce neurological sequelae or on the macrophages/microglia that are associated with development of encephalitis, the molecular signaling pathways within the BMECs involved have yet to be resolved. We have previously shown that there is activation and disruption of an in vitro BBB model using lentivirus-infected CEMx174 cells. We and others have shown similar disruption in vivo. Therefore, it was of interest to determine if the presence of infected cells could disrupt intact cerebral microvessels immediately ex vivo, and if so, which signaling pathways were involved. The present data demonstrate that disruption of tight junctions between BMECs is mediated through activation of focal adhesion kinase (FAK) by phosphorylation at TYR-397. Inhibition of FAK activation is sufficient to prevent tight junction disruption. Thus, it may be possible to inhibit the development of HIVE by using inhibitors of FAK.
Ivey
Nathan S
NS
Tulane Primate Center, Pathology, Covington, LA 70433, USA.
Renner
Nicole A
NA
Moroney-Rasmussen
Terri
T
Mohan
Mahesh
M
Redmann
Rachel K
RK
Didier
Peter J
PJ
Alvarez
Xavier
X
Lackner
Andrew A
AA
MacLean
Andrew G
AG
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000648:ultrastructure / Q000821:virology; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D018792:Encephalitis, Viral / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008253:Macaca mulatta; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D055806:Microvessels / Q000378:metabolism / Q000821:virology; D009000:Monocytes / Q000821:virology; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D015302:Simian Immunodeficiency Virus; D019108:Tight Junctions / Q000473:pathology / Q000821:virology*; D062826:Zonula Occludens-1 Protein
D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D051417:Focal Adhesion Kinase 1