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PMID: 10430614 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Role of the tyrosine kinase pyk2 in the integrin-dependent activation of human neutrophils by TNF.

The Journal of clinical investigation ·Vol. 104 ·No. 3 ·1999-08-00 ·Pages 327-35

Fuortes M, Melchior M, Han H, Lyon GJ, Nathan C

Abstract

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.

MeSH Terms
Androstadienes/pharmacology Cell Adhesion/drug effects,immunology Cell Size/drug effects,immunology Cytoskeletal Proteins/metabolism Enzyme Inhibitors/pharmacology Focal Adhesion Kinase 2 Humans Integrins/physiology Neutrophil Activation/drug effects,immunology Neutrophils/drug effects,enzymology,immunology Nitriles Paxillin Phosphoprotein Phosphatases/antagonists & inhibitors Phosphoproteins/metabolism Phosphorylation/drug effects Protein-Tyrosine Kinases/antagonists & inhibitors,physiology Tetradecanoylphorbol Acetate/pharmacology Tumor Necrosis Factor-alpha/physiology Tyrosine/metabolism Tyrphostins/pharmacology Wortmannin
Chemicals
Androstadienes Cytoskeletal Proteins Enzyme Inhibitors Integrins Nitriles PXN protein, human Paxillin Phosphoproteins Tumor Necrosis Factor-alpha Tyrphostins Tyrosine SF 6847 Protein-Tyrosine Kinases Focal Adhesion Kinase 2 Phosphoprotein Phosphatases Tetradecanoylphorbol Acetate Wortmannin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Fuortes 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
Han H
Lyon G J
Nathan C
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI6018
Email
mfuortes@med.cornell.edu
Published
1999-08-00
Pages
327-35
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC408415
Subset
IM
Grants
NIGMS NIH HHS · T32 GM007739 · United States
NCI NIH HHS · CAAI45218 · United States
NIGMS NIH HHS · GM07739 · United States
External Links
PubMed source DOI: 10.1172/JCI6018 PMC Full Text View journal details
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