title: Role of Cingulin in Agonist-induced Vascular Endothelial Permeability.
abstract: Agonist-induced activation of Rho GTPase signaling leads to endothelial cell (EC) permeability and may culminate in pulmonary edema, a devastating complication of acute lung injury. Cingulin is an adaptor protein first discovered in epithelium and is involved in the organization of the tight junctions. This study investigated the role of cingulin in control of agonist-induced lung EC permeability via interaction with RhoA-specific activator GEF-H1. The siRNA-induced cingulin knockdown augmented thrombin-induced EC permeability monitored by measurements of transendothelial electrical resistance and endothelial cell permeability for macromolecules. Increased thrombin-induced permeability in ECs with depleted cingulin was associated with increased activation of GEF-H1 and RhoA detected in pulldown activation assays. Increased GEF-H1 association with cingulin was essential for down-regulation of thrombin-induced RhoA barrier disruptive signaling. Using cingulin-truncated mutants, we determined that GEF-H1 interaction with the rod + tail domain of cingulin was required for inactivation of GEF-H1 and endothelial cell barrier preservation. The results demonstrate the role for association of GEF-H1 with cingulin as the mechanism of RhoA pathway inactivation and rescue of EC barrier after agonist challenge.
authors: From the Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637 and.
authors: Yufeng
authors: Y
authors: Tian
authors: From the Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637 and.
authors: Grzegorz
authors: G
authors: Gawlak
authors: From the Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637 and.
authors: Xinyong
authors: X
authors: Tian
authors: From the Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637 and.
authors: Alok S
authors: AS
authors: Shah
authors: From the Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637 and.
authors: Nicolene
authors: N
authors: Sarich
authors: the Department of Cell Biology, University of Geneva, 1205 Geneva, Switzerland.
authors: Sandra
authors: S
authors: Citi
authors: From the Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637 and abirukov@medicine.bsd.uchicago.edu.
authors: Anna A
authors: AA
authors: Birukova
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002199:Capillary Permeability; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D060066:Protein Interaction Maps; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C577356:ARHGEF2 protein, human; C061407:CGN protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; C066737:RHOA protein, human; D013917:Thrombin; D020742:rhoA GTP-Binding Protein
keywords: Rho (Rho GTPase); endothelium; lung injury; permeability; signal transduction; vascular biology