Role of the tyrosine kinase pyk2 in the integrin-dependent activation of human neutrophils by TNF.
Secretion of inflammatory products from neutrophils can be induced by a combination of signals from ligated integrins and receptors for soluble, physiological agonists such as TNF. Here we identify pyk2 in primary human neutrophils; localize it to focal adhesions and podosomes; and demonstrate its tyrosine phosphorylation, activation, and association with paxillin during stimulation of adherent cells by TNF. Tyrphostin A9 emerged as the most potent and selective of 51 tyrosine kinase inhibitors tested against the TNF-induced respiratory burst. Tyrphostin A9 inhibited TNF-induced tyrosine phosphorylation of pyk2 without blocking the cells' bactericidal activity. Wortmannin, an inhibitor of phosphatidylinositol-3-kinase, potently blocked the TNF-induced respiratory burst and selectively inhibited tyrosine phosphorylation of pyk2. Thus, pyk2 appears to play an essential role in the ability of neutrophils to integrate signals from beta(2) integrins and TNF receptors.
Fuortes
M
M
Department of Cell Biology, Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York 10021, USA. mfuortes@med.cornell.edu
Melchior
M
M
Han
H
H
Lyon
G J
GJ
Nathan
C
C
D000730:Androstadienes / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D048429:Cell Size / Q000187:drug effects / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D006801:Humans; D016023:Integrins / Q000502:physiology*; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D009570:Nitriles; D051419:Paxillin; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D016023:Integrins; D009570:Nitriles; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; D014443:Tyrosine; C001784:SF 6847; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; D010749:Phosphoprotein Phosphatases; D013755:Tetradecanoylphorbol Acetate; D000077191:Wortmannin