Neutrophil direction sensing and superoxide production linked by the GTPase-activating protein GIT2.
In neutrophils, superoxide anion production generally accompanies chemotaxis and functions in killing invading pathogens. The GIT2 GTPase-activating protein binds to the guanine nucleotide-exchange factor alphaPIX. Here we show that GIT2 was necessary for directional chemotaxis and for the suppression of superoxide production in G protein-coupled receptor-stimulated neutrophils. GIT2 was also necessary for the orientation of superoxide production toward chemoattractant sources. GIT2 suppressed the activity of ADP ribosylation factor 1 and was a component of the Gbetagamma subunit-mediated direction-sensing machinery 'downstream' of G protein-coupled receptor signaling. This study establishes a function for GIT2 in linking chemotaxis and superoxide production in neutrophils and shows that loss of GIT2 in vivo leads to an immunodeficient state.
Mazaki
Yuichi
Y
Department of Molecular Biology, Osaka Bioscience Institute, Suita 565-0874, Japan.
Hashimoto
Shigeru
S
Tsujimura
Tohru
T
Morishige
Masaki
M
Hashimoto
Ari
A
Aritake
Kosuke
K
Yamada
Atsuko
A
Nam
Jin-Min
JM
Kiyonari
Hiroshi
H
Nakao
Kazuki
K
Sabe
Hisataka
H
D020823:ADP-Ribosylation Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001228:Aspergillosis / Q000276:immunology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D015936:Complement C5a / Q000494:pharmacology; D004198:Disease Susceptibility; D004789:Enzyme Activation; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D013481:Superoxides / Q000378:metabolism*; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D018797:Cell Cycle Proteins; D002630:Chemotactic Factors; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D020690:GTPase-Activating Proteins; C120767:Git2 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D046912:Multiprotein Complexes; D018129:Phosphatidylinositol Phosphates; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C060974:phosphatidylinositol 3,4,5-triphosphate; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D020823:ADP-Ribosylation Factor 1; D020830:rac1 GTP-Binding Protein