title: Phosphoinositide 3-OH kinase regulates integrin-dependent processes in neutrophils by signaling through its effector ARAP3.
abstract: ARAP3, a GTPase activating protein for Rho and Arf family GTPases, is one of many phosphoinositide 3-OH kinase (PI3K) effectors. In this study, we investigate the regulatory input of PI3K upstream of ARAP3 by analyzing neutrophils from an ARAP3 pleckstrin homology (PH) domain point mutation knock-in mouse (R302, 303A), in which ARAP3 is uncoupled from activation by PI3K. ARAP3 PH domain point mutant neutrophils are characterized by disturbed responses linked to stimulation by either integrin ligands or immobilized immune complexes. These cells exhibit increased β2 integrin inside-out signaling (binding affinity and avidity), and our work suggests the disturbed responses to immobilized immune complexes are secondary to this. In vitro, neutrophil chemotaxis is affected in the mutant. In vivo, ARAP3 PH domain point mutant bone marrow chimeras exhibit reduced neutrophil recruitment to the peritoneum on induction of sterile peritonitis and also reduced inflammation in a model for rheumatoid arthritis. The current work suggests a dramatic regulatory input of PI3K into the regulation of β2 integrin activity, and processes dependent on this, by signaling through its effector ARAP3.
authors.affiliation: The Inositide Laboratory, The Babraham Institute, Cambridge CB22 3AT, United Kingdom.
authors.forename: Laure
authors.initials: L
authors.lastname: Gambardella
authors.forename: Karen E
authors.initials: KE
authors.lastname: Anderson
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Jakus
authors.forename: Miklós
authors.initials: M
authors.lastname: Kovács
authors.forename: Susann
authors.initials: S
authors.lastname: Voigt
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Hawkins
authors.forename: Len
authors.initials: L
authors.lastname: Stephens
authors.forename: Attila
authors.initials: A
authors.lastname: Mócsai
authors.forename: Sonja
authors.initials: S
authors.lastname: Vermeren
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism* / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055879:Gene Knock-In Techniques; D008024:Ligands; D051379:Mice; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis; D017354:Point Mutation; D015290:Second Messenger Systems / Q000235:genetics / Q000276:immunology
chemical_list: C446512:ARAP3 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018821:CD18 Antigens; D020690:GTPase-Activating Proteins; D008024:Ligands; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D058539:Phosphatidylinositol 3-Kinase