Tiam1 and betaPIX mediate Rac-dependent endothelial barrier protective response to oxidized phospholipids

Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) exhibits potent barrier protective effects on pulmonary endothelium, which are mediated by small GTPases Rac and Cdc42. However, upstream mechanisms of OxPAPC-induced small GTPase activation are not known. We studied involve...

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Bibliographic Details
Published in:Journal of cellular physiology 2007-06, Vol.211 (3), p.608-617
Main Authors: Birukova, Anna A, Malyukova, Irina, Mikaelyan, Arsen, Fu, Panfeng, Birukov, Konstantin G
Format: Article
Language:English
Subjects:
Capillary Permeability - drug effects
Capillary Permeability - physiology
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cells, Cultured
Cytoskeleton - drug effects
Cytoskeleton - metabolism
Electric Impedance
Endothelial Cells - cytology
Endothelial Cells - metabolism
Guanine Nucleotide Exchange Factors - genetics
Guanine Nucleotide Exchange Factors - metabolism
Humans
Monomeric GTP-Binding Proteins - metabolism
Oxidation-Reduction
p21-Activated Kinases
Phosphatidylcholines - pharmacology
Protein-Serine-Threonine Kinases - metabolism
Pulmonary Artery - cytology
rac GTP-Binding Proteins - metabolism
Rho Guanine Nucleotide Exchange Factors - metabolism
RNA, Small Interfering
T-Lymphoma Invasion and Metastasis-inducing Protein 1
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Summary:Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) exhibits potent barrier protective effects on pulmonary endothelium, which are mediated by small GTPases Rac and Cdc42. However, upstream mechanisms of OxPAPC-induced small GTPase activation are not known. We studied involvement of Rac/Cdc42-specific guanine nucleotide exchange factors (GEFs) Tiam1 and betaPIX in OxPAPC-induced Rac activation, cytoskeletal remodeling, and barrier protective responses in the human pulmonary endothelial cells (EC). OxPAPC induced membrane translocation of Tiam1, betaPIX, Cdc42, and Rac, but did not affect intracellular distribution of Rho and Rho-specific GEF p115-RhoGEF. Protein depletion of Tiam1 and betaPIX using siRNA approach abolished OxPAPC-induced activation of Rac and its effector PAK1. EC transfection with Tiam1-, betaPIX-, or PAK1-specific siRNA dramatically attenuated OxPAPC-induced barrier enhancement, peripheral actin cytoskeletal enhancement, and translocation of actin-binding proteins cortactin and Arp3. These results show for the first time that Tiam1 and betaPIX mediate OxPAPC-induced Rac activation, cytoskeletal remodeling, and barrier protective response in pulmonary endothelium.
ISSN:0021-9541