A tyrosine kinase signaling pathway accounts for the majority of phosphatidylinositol 3,4,5-trisphosphate formation in chemoattractant-stimulated human neutrophils.
The signaling pathway leading from G protein-coupled chemoattractant receptors to the generation of oxidants by NADPH oxidase in human neutrophils requires the formation of the lipid mediator phosphatidylinositol 3,4,5-trisphosphate (PIP3). Two mechanisms through which PIP3 can be generated have been described in human leukocytes. One pathway involves the coupling of the src-related tyrosine kinase Lyn to the "classical" p85/p110 form of phosphatidylinositol 3-kinase. The second paradigm utilizes a novel form of phosphatidylinositol 3-kinase whose activity is directly regulated by G protein betagamma subunits. In this paper, we show that formation of PIP3 in chemoattractant-stimulated neutrophils is substantially attenuated by inhibitors that specifically block tyrosine kinase activity. These data suggest that the Lyn activation pathway plays a major role in the formation of this important lipid messenger during chemoattractant stimulation of human neutrophils.
Ptasznik
A
A
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Prossnitz
E R
ER
Yoshikawa
D
D
Smrcka
A
A
Traynor-Kaplan
A E
AE
Bokoch
G M
GM
D002634:Chemotaxis, Leukocyte; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates / Q000097:blood*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000097:blood / Q000302:isolation & purification; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000097:blood*; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D007529:Isoflavones; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019833:Genistein; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins