title: Rac regulates PtdInsP₃ signaling and the chemotactic compass through a redox-mediated feedback loop.
abstract: Directional cell migration is an essential requirement for efficient neutrophil translocation to sites of infection and requires the establishment of a polarized cell characterized by an actin-rich leading edge facing the chemoattractant gradient. The asymmetrical accumulation of phosphatidylinositol(3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)] in the up-gradient leading edge is a hallmark of polarization and regulates the recruitment and localization of various effector proteins at the leading-edge plasma membrane. How shallow gradients of chemoattractants trigger and maintain a much steeper intracellular gradient of PtdIns(3,4,5)P(3) is a critical question in the study of leukocyte chemotaxis. Our data demonstrate that the migration of neutrophils toward the chemoattractant N-formyl-L-methionyl-L-leucyl-L-phenylalanine depends on the generation of reactive oxygen species by the phagocytic NADPH oxidase (NOX2) and subsequent oxidation and inhibition of phosphatase and tensin homolog. Moreover, we show that events downstream of PtdIns(3,4,5)P(3), including phosphorylation of AKT, Rac activation, uncapping of actin filaments, and directional migration, can be attenuated by ROS scavengers or genetic ablation of NOX2. Using Rac mutants that are defective in their ability to activate NOX2, we show that Rac regulates a redox-mediated feedback loop that mediates directional migration of neutrophils.
authors: Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada. jan.kuiper@utoronto.ca
authors: Jan W P
authors: JW
authors: Kuiper
authors: Chunxiang
authors: C
authors: Sun
authors: Marco A O
authors: MA
authors: Magalhães
authors: Michael
authors: M
authors: Glogauer
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism*; D010084:Oxidation-Reduction; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
chemical_list: D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009479:Neuropeptides; D018129:Phosphatidylinositol Phosphates; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse; C060974:phosphatidylinositol 3,4,5-triphosphate; C488842:Cybb protein, mouse; C514862:Akt1 protein, mouse