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(Received for publication, August 8, 1996, and in revised form, October 16, 1996)
From the Activation of polymorphonuclear leukocytes (PMN)
by chemotactic peptides initiates a series of functional responses that
serve to eliminate pathogens. The intermediate steps that link
engagement of the chemoattractant receptor to the microbicidal
responses involve protein kinases that have yet to be identified. In
this study we detected in human PMN the presence of p38
mitogen-activated protein kinase (MAPK), which became rapidly tyrosine
phosphorylated and activated in response to the chemotactic peptide
N-formyl-methionyl-leucyl-phenylalanine (fMLP).
Pretreatment of PMN with wortmannin, a phosphatidylinositol 3-kinase
inhibitor, or bis-indolylmaleimide, a protein kinase C
antagonist, resulted in partial inhibition of p38 phosphorylation upon
fMLP stimulation. Similarly, phosphorylation of p38 was only partially
inhibited when the fMLP-induced cytosolic calcium transient was
prevented. Stimulation of PMN by the chemoattractant also resulted in
the rapid phosphorylation and activation of MAPK-activated protein
kinase-2 (MAPKAPK-2), which was completely inhibited by the specific
p38 inhibitor, SB203580. The physical interaction of p38 with MAPKAPK-2
was studied by coimmunoprecipitation. These two kinases were found to
be associated in unstimulated PMN but dissociated upon activation of
the cells by fMLP. Together these findings demonstrate the activation
of p38 by chemotactic peptides in human PMN by a process involving
phosphatidylinositol 3-kinase, protein kinase C, and calcium. p38, in
turn, is an upstream activator of MAPKAPK-2.
Volume 272, Number 2,
Issue of January 10, 1997
pp. 937-944
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
,
and
Division of Cell Biology, Research
Institute, The Hospital for Sick Children and the 
Department of
Biochemistry, University of Toronto, Toronto, Ontario M5G 1X8, Canada
and the ¶ Department of Medicine, University of British
Columbia, and Kinetek Pharmaceuticals Inc., Vancouver,
British Columbia V5Z 1A1, Canada
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M. J. Rane, J. M. Arthur, E. R. Prossnitz, and K. R. McLeish Activation of Mitogen-activated Protein Kinases by Formyl Peptide Receptors Is Regulated by the Cytoplasmic Tail J. Biol. Chem., August 14, 1998; 273(33): 20916 - 20923. [Abstract] [Full Text] [PDF]
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 A. Clerk, A. Michael, and P. H. Sugden Stimulation of the p38 Mitogen-activated Protein Kinase Pathway in Neonatal Rat Ventricular Myocytes by the G Protein-coupled Receptor Agonists, Endothelin-1 and Phenylephrine: A Role in Cardiac Myocyte Hypertrophy? J. Cell Biol., July 27, 1998; 142(2): 523 - 535. [Abstract] [Full Text] [PDF]
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M. Ushio-Fukai, R. W. Alexander, M. Akers, and K. K. Griendling p38 Mitogen-activated Protein Kinase Is a Critical Component of the Redox-sensitive Signaling Pathways Activated by Angiotensin II. ROLE IN VASCULAR SMOOTH MUSCLE CELL HYPERTROPHY J. Biol. Chem., June 12, 1998; 273(24): 15022 - 15029. [Abstract] [Full Text] [PDF]
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D. Sheikh-Hamad, J. Di Mari, W. N. Suki, R. Safirstein, B. A. Watts III, and D. Rouse p38 Kinase Activity Is Essential for Osmotic Induction of mRNAs for HSP70 and Transporter for Organic Solute Betaine in Madin-Darby Canine Kidney Cells J. Biol. Chem., January 16, 1998; 273(3): 1832 - 1837. [Abstract] [Full Text] [PDF]
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K.-D. Chen, L.-Y. Chen, H.-L. Huang, C.-H. Lieu, Y.-N. Chang, M. D.-T. Chang, and Y.-K. Lai Involvement of p38 Mitogen-activated Protein Kinase Signaling Pathway in the Rapid Induction of the 78-kDa Glucose-regulated Protein in 9L Rat Brain Tumor Cells J. Biol. Chem., January 9, 1998; 273(2): 749 - 755. [Abstract] [Full Text] [PDF]
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G. P. Downey, J. R. Butler, H. Tapper, L. Fialkow, A. R. Saltiel, B. B. Rubin, and S. Grinstein Importance of MEK in Neutrophil Microbicidal Responsiveness J. Immunol., January 1, 1998; 160(1): 434 - 443. [Abstract] [Full Text] [PDF]
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J. Yamauchi, M. Nagao, Y. Kaziro, and H. Itoh Activation of p38 Mitogen-activated Protein Kinase by Signaling through G Protein-coupled Receptors. INVOLVEMENT OF Gbeta gamma AND Galpha q/11 SUBUNITS J. Biol. Chem., October 31, 1997; 272(44): 27771 - 27777. [Abstract] [Full Text] [PDF]
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E. Krump, K. Nikitas, and S. Grinstein Induction of Tyrosine Phosphorylation and Na+/H+ Exchanger Activation during Shrinkage of Human Neutrophils J. Biol. Chem., July 11, 1997; 272(28): 17303 - 17311. [Abstract] [Full Text] [PDF]
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P. H. Naccache, S. Levasseur, G. Lachance, S. Chakravarti, S. G. Bourgoin, and S. R. McColl Stimulation of Human Neutrophils by Chemotactic Factors Is Associated with the Activation of Phosphatidylinositol 3-Kinase gamma J. Biol. Chem., July 28, 2000; 275(31): 23636 - 23641. [Abstract] [Full Text] [PDF]
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R. A. Ward, M. Nakamura, and K. R. McLeish Priming of the Neutrophil Respiratory Burst Involves p38 Mitogen-activated Protein Kinase-dependent Exocytosis of Flavocytochrome b558-containing Granules J. Biol. Chem., November 17, 2000; 275(47): 36713 - 36719. [Abstract] [Full Text] [PDF]
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M. J. Rane, P. Y. Coxon, D. W. Powell, R. Webster, J. B. Klein, W. Pierce, P. Ping, and K. R. McLeish p38 Kinase-dependent MAPKAPK-2 Activation Functions as 3-Phosphoinositide-dependent Kinase-2 for Akt in Human Neutrophils J. Biol. Chem., January 26, 2001; 276(5): 3517 - 3523. [Abstract] [Full Text] [PDF]
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S. Bechoua and L. W. Daniel Phospholipase D Is Required in the Signaling Pathway Leading to p38 MAPK Activation in Neutrophil-like HL-60 Cells, Stimulated by N-Formyl-methionyl-leucyl-phenylalanine J. Biol. Chem., August 17, 2001; 276(34): 31752 - 31759. [Abstract] [Full Text] [PDF]
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J. E. Smolen, T. K. Petersen, C. Koch, S. J. O'Keefe, W. A. Hanlon, S. Seo, D. Pearson, M. C. Fossett, and S. I. Simon L-Selectin Signaling of Neutrophil Adhesion and Degranulation Involves p38 Mitogen-activated Protein Kinase J. Biol. Chem., May 19, 2000; 275(21): 15876 - 15884. [Abstract] [Full Text] [PDF]
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O. Werz, J. Klemm, B. Samuelsson, and O. Radmark 5-Lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases PNAS, May 9, 2000; 97(10): 5261 - 5266. [Abstract] [Full Text] [PDF]
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