title: A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress.
abstract: Hemodynamic forces regulate embryonic organ development, hematopoiesis, vascular remodeling, and atherogenesis. The mechanosensory stimulus of blood flow initiates a complex network of intracellular pathways, including activation of Rac1 GTPase, establishment of endothelial cell (EC) polarity, and redox signaling. The activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can be modulated by the GTP/GDP state of Rac1; however, the molecular mechanisms of Rac1 activation by flow are poorly understood. Here, we identify a novel polarity complex that directs localized Rac1 activation required for downstream reactive oxygen species (ROS) production. Vav2 is required for Rac1 GTP loading, whereas, surprisingly, Tiam1 functions as an adaptor in a VE-cadherin-p67phox-Par3 polarity complex that directs localized activation of Rac1. Furthermore, loss of Tiam1 led to the disruption of redox signaling both in vitro and in vivo. Our results describe a novel molecular cascade that regulates redox signaling by the coordinated regulation of Rac1 and by linking components of the polarity complex to the NADPH oxidase.
authors.affiliation: Department of Cell Biology and Physiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yunhao
authors.initials: Y
authors.lastname: Liu
authors.forename: Caitlin
authors.initials: C
authors.lastname: Collins
authors.forename: William B
authors.initials: WB
authors.lastname: Kiosses
authors.forename: Ann M
authors.initials: AM
authors.lastname: Murray
authors.forename: Monika
authors.initials: M
authors.lastname: Joshi
authors.forename: Tyson R
authors.initials: TR
authors.lastname: Shepherd
authors.forename: Ernesto J
authors.initials: EJ
authors.lastname: Fuentes
authors.forename: Ellie
authors.initials: E
authors.lastname: Tzima
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001011:Aorta / Q000502:physiology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013314:Stress, Mechanical; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D015820:Cadherins; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D009479:Neuropeptides; D010750:Phosphoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D034741:RNA, Small Interfering; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000099152:Cadherin 5; C509689:PARD3 protein, human; C115084:Pard3 protein, mouse; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; C087334:TIAM1 protein, human; C513260:Tiam1 protein, mouse; C079789:neutrophil cytosol factor 67K