title: IQGAP1 is necessary for pulmonary vascular barrier protection in murine acute lung injury and pneumonia.
abstract: We recently reported that integrin α(v)β(3) is necessary for vascular barrier protection in mouse models of acute lung injury and peritonitis. Here, we used mass spectrometric sequencing of integrin complexes to isolate the novel β(3)-integrin binding partner IQGAP1. Like integrin β(3), IQGAP1 localized to the endothelial cell-cell junction after sphingosine-1-phosphate (S1P) treatment, and IQGAP1 knockdown prevented cortical actin formation and barrier enhancement in response to S1P. Furthermore, knockdown of IQGAP1 prevented localization of integrin α(v)β(3) to the cell-cell junction. Similar to β(3)-null animals, IQGAP1-null mice had increased pulmonary vascular leak compared with wild-type controls 3 days after intratracheal LPS. In an Escherichia coli pneumonia model, IQGAP1 knockout mice had increased lung weights, lung water, and lung extravascular plasma equivalents of (125)I-labeled albumin compared with wild-type controls. Taken together, these experiments indicate that IQGAP1 is necessary for S1P-mediated vascular barrier protection during acute lung injury and is required for junctional localization of the barrier-protective integrin α(v)β(3).
authors.affiliation: Lung Biology Center, UCSF, Rock Hall, Rm. 545, 1550 4th St., San Francisco, CA 94158, USA. mallar.bhattacharya@ucsf.edu
authors.forename: M
authors.initials: M
authors.lastname: Bhattacharya
authors.forename: G
authors.initials: G
authors.lastname: Su
authors.forename: X
authors.initials: X
authors.lastname: Su
authors.forename: J A
authors.initials: JA
authors.lastname: Oses-Prieto
authors.forename: J T
authors.initials: JT
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.forename: H
authors.initials: H
authors.lastname: Hernandez
authors.forename: A
authors.initials: A
authors.lastname: Atakilit
authors.forename: A L
authors.initials: AL
authors.lastname: Burlingame
authors.forename: M A
authors.initials: MA
authors.lastname: Matthay
authors.forename: D
authors.initials: D
authors.lastname: Sheppard
mesh_terms: D000199:Actins / Q000378:metabolism; D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; C101203:IQ motif containing GTPase activating protein 1; D039302:Integrin alphaVbeta3; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D020703:ras GTPase-Activating Proteins; C060506:sphingosine 1-phosphate; D013110:Sphingosine