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*
Institute of General Pathology, University of Verona, Verona, Italy;
Department of Physiology and Laboratory of Cellular and Molecular Physiology, Semmelweis University of Medicine, Budapest, Hungary; and
Department of Laboratory Medicine, University of California, San Francisco, CA 94143
Polymorphonuclear neutrophils (PMN) adherent to integrin ligands
respond to inflammatory mediators by reorganizing their cytoskeleton
and releasing reactive oxygen intermediates. As Src family tyrosine
kinases are implicated in these responses, we investigated their
possible role in regulating degranulation. Human PMN incubated on
fibrinogen released lactoferrin in response to TNF-
and this
response was inhibited by PP1, a Src family tyrosine kinase inhibitor.
This drug had no effect on lactoferrin secretion induced by PMA, an
adhesion-independent agonist of PMN degranulation. However, PP1 blocked
secretion in PMN plated on plain tissue culture plastic, a surface
inducing PMN spreading in the absence of any stimulus. Double knockout
hck-/-fgr-/-
PMN adherent to collagen or fibrinogen failed to release lactoferrin in
response to TNF- but responded to PMA as wild-type PMN.
Degranulation induced by spreading over tissue culture plastic was also
defective in
hck-/-fgr-/-
PMN. Defective adhesion-dependent degranulation required the absence of
both kinases, because single knockout
fgr-/- or
hck-/- PMN responded as wild-type cells.
Analysis of lactoferrin secretion in
hck-/-fgr-/-
or PP1-treated, suspended PMN showed that Src kinases are not
implicated in degranulation dependent on activation of protein kinase C
or increase in intracellular free Ca2+ but may play a role
in the response to FMLP of cytochalasin B-treated PMN. These findings
identify a role for Src family kinases in a signaling pathway leading
to granule-plasma membrane fusion and suggest that Fgr and Hck would be
targets for pharmacological control of adhesion-dependent degranulation
in the inflammatory site.
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L. Tatton, G. M. Morley, R. Chopra, and A. Khwaja The Src-selective Kinase Inhibitor PP1 Also Inhibits Kit and Bcr-Abl Tyrosine Kinases J. Biol. Chem., February 7, 2003; 278(7): 4847 - 4853. [Abstract] [Full Text] [PDF]
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M. Ernst, M. Inglese, G. M. Scholz, K. W. Harder, F. J. Clay, S. Bozinovski, P. Waring, R. Darwiche, T. Kay, P. Sly, et al. Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response J. Exp. Med., September 2, 2002; 196(5): 589 - 604. [Abstract] [Full Text] [PDF]
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M. P. Scott, F. Zappacosta, E. Y. Kim, R. S. Annan, and W. T. Miller Identification of Novel SH3 Domain Ligands for the Src Family Kinase Hck. WISKOTT-ALDRICH SYNDROME PROTEIN (WASP), WASP-INTERACTING PROTEIN (WIP), AND ELMO1 J. Biol. Chem., July 26, 2002; 277(31): 28238 - 28246. [Abstract] [Full Text] [PDF]
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L. Vicentini, P. Mazzi, E. Caveggion, S. Continolo, L. Fumagalli, J. A. Lapinet-Vera, C. A. Lowell, and G. Berton Fgr Deficiency Results in Defective Eosinophil Recruitment to the Lung During Allergic Airway Inflammation J. Immunol., June 15, 2002; 168(12): 6446 - 6454. [Abstract] [Full Text] [PDF]
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C. Rubel, G. C. Fernandez, F. A. Rosa, S. Gomez, M. B. Bompadre, O. A. Coso, M. A. Isturiz, and M. S. Palermo Soluble Fibrinogen Modulates Neutrophil Functionality Through the Activation of an Extracellular Signal-Regulated Kinase-Dependent Pathway J. Immunol., April 1, 2002; 168(7): 3527 - 3535. [Abstract] [Full Text] [PDF]
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E. Nijhuis, J.-W. J Lammers, L. Koenderman, and P. J. Coffer Src kinases regulate PKB activation and modulate cytokine and chemoattractant-controlled neutrophil functioning J. Leukoc. Biol., January 1, 2002; 71(1): 115 - 124. [Abstract] [Full Text] [PDF]
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 J. H. Lee, N. Kaminski, G. Dolganov, G. Grunig, L. Koth, C. Solomon, D. J. Erle, and D. Sheppard Interleukin-13 Induces Dramatically Different Transcriptional Programs in Three Human Airway Cell Types Am. J. Respir. Cell Mol. Biol., October 1, 2001; 25(4): 474 - 485. [Abstract] [Full Text] [PDF]
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P. Piccardoni, R. Sideri, S. Manarini, A. Piccoli, N. Martelli, G. de Gaetano, C. Cerletti, and V. Evangelista Platelet/polymorphonuclear leukocyte adhesion: a new role for SRC kinases in Mac-1 adhesive function triggered by P-selectin Blood, July 1, 2001; 98(1): 108 - 116. [Abstract] [Full Text] [PDF]
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 C. L. Smith, P. Mittaud, E. D. Prescott, C. Fuhrer, and S. J. Burden Src, Fyn, and Yes Are Not Required for Neuromuscular Synapse Formation But Are Necessary for Stabilization of Agrin-Induced Clusters of Acetylcholine Receptors J. Neurosci., May 1, 2001; 21(9): 3151 - 3160. [Abstract] [Full Text] [PDF]
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S. Pereira, M. Zhou, A. Mocsai, and C. Lowell Resting Murine Neutrophils Express Functional {{alpha}}4 Integrins that Signal Through Src Family Kinases J. Immunol., March 15, 2001; 166(6): 4115 - 4123. [Abstract] [Full Text] [PDF]
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C. Rubel, G. C. Fernandez, G. Dran, M. B. Bompadre, M. A. Isturiz, and M. S. Palermo Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis J. Immunol., February 1, 2001; 166(3): 2002 - 2010. [Abstract] [Full Text] [PDF]
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S. Verploegen, J.-W. J. Lammers, L. Koenderman, and P. J. Coffer Identification and characterization of CKLiK, a novel granulocyte Ca++/calmodulin-dependent kinase Blood, November 1, 2000; 96(9): 3215 - 3223. [Abstract] [Full Text] [PDF]
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R. Menegazzi, S. Busetto, R. Cramer, P. Dri, and P. Patriarca Role of Intracellular Chloride in the Reversible Activation of Neutrophil {beta}2 Integrins: A Lesson from TNF Stimulation J. Immunol., October 15, 2000; 165(8): 4606 - 4614. [Abstract] [Full Text] [PDF]
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A. Mocsai, Z. Jakus, T. Vantus, G. Berton, C. A. Lowell, and E. Ligeti Kinase Pathways in Chemoattractant-Induced Degranulation of Neutrophils: The Role of p38 Mitogen-Activated Protein Kinase Activated by Src Family Kinases J. Immunol., April 15, 2000; 164(8): 4321 - 4331. [Abstract] [Full Text] [PDF]
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 P. Suen, D Ilic, E Caveggion, G Berton, C. Damsky, and C. Lowell Impaired integrin-mediated signal transduction, altered cytoskeletal structure and reduced motility in Hck/Fgr deficient macrophages J. Cell Sci., January 11, 1999; 112(22): 4067 - 4078. [Abstract] [PDF]
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S. Carreno, M.-E. Gouze, S. Schaak, L. J. Emorine, and I. Maridonneau-Parini Lack of Palmitoylation Redirects p59Hck from the Plasma Membrane to p61Hck-positive Lysosomes J. Biol. Chem., November 10, 2000; 275(46): 36223 - 36229. [Abstract] [Full Text] [PDF]
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S. Sergeant, K. A. Waite, J. Heravi, and L. C. McPhail Phosphatidic Acid Regulates Tyrosine Phosphorylating Activity in Human Neutrophils. ENHANCEMENT OF Fgr ACTIVITY J. Biol. Chem., February 9, 2001; 276(7): 4737 - 4746. [Abstract] [Full Text] [PDF]
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P. Peyron, I. Maridonneau-Parini, and T. Stegmann Fusion of Human Neutrophil Phagosomes with Lysosomes in Vitro. INVOLVEMENT OF TYROSINE KINASES OF THE Src FAMILY AND INHIBITION BY MYCOBACTERIA J. Biol. Chem., September 14, 2001; 276(38): 35512 - 35517. [Abstract] [Full Text] [PDF]
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