Journal
JOURNAL OF IMMUNOLOGY
Volume 176, Issue 2, Pages 1218-1227Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.176.2.1218
Keywords
-
Categories
Funding
- NHLBI NIH HHS [HL48160, HL070009] Funding Source: Medline
Ask authors/readers for more resources
Endothelial cells (ECs) respond to TNF-alpha by altering their F-actin cytoskeleton and junctional permeability through mechanisms that include protein kinase C (PKC) and p38 MAPK. Ezrin, radixin, and moesin (ERM) regulate many cell processes that often require a conformational change of these proteins as a result of phosphorylation on a conserved threonine residue near the C terminus. This study tested the hypothesis that ERM proteins are phosphorylated on this critical threonine residue through TNF-alpha-induced activation of PKC and p38 and modulate permeability increases in pulmonary microvascular ECs. TNF-a induced ERM phosphorylation on the threonine residue that required activation of p38, PKC isoforms, and phosphatidylinositol-4-phosphate 5-kinase I alpha, a major enzyme generating phosphatidylinositol 4,5-bisphosphate, and phosphorylated ERM were prominently localized at the EC periphery. TNF-a-induced ERM phosphorylation was accompanied by cytoskeletal changes, paracellular gap formation, and increased permeability to fluxes of dextran and albumin. These changes required activation of p38 and PKC and were completely prevented by inhibition of ERM protein expression using small interfering RNA. Thus, ERM proteins are phosphorylated through p38 and PKC-dependent mechanisms and modulate TNF-a-induced increases in endothelial permeability. Phosphorylation of ERM likely plays important roles in EC responses to TNF-a by modulating the F-actin cytoskeleton, adhesion molecules, and signaling events.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available