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Science 11 February 2000:
Vol. 287. no. 5455, pp. 1049 - 1053
DOI: 10.1126/science.287.5455.1049
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Reports

Central Role for G Protein-Coupled Phosphoinositide 3-Kinase gamma  in Inflammation

Emilio Hirsch, 1* Vladimir L. Katanaev, 2 Cecilia Garlanda, 3 Ornella Azzolino, 1 Luciano Pirola, 2 Lorenzo Silengo, 1 Silvano Sozzani, 3 Alberto Mantovani, 34 Fiorella Altruda, 1dagger Matthias P. Wymann 2*dagger

Phosphoinositide 3-kinase (PI3K) activity is crucial for leukocyte function, but the roles of the four receptor-activated isoforms are unclear. Mice lacking heterotrimeric guanine nucleotide-binding protein (G protein)-coupled PI3Kgamma were viable and had fully differentiated neutrophils and macrophages. Chemoattractant-stimulated PI3Kgamma -/- neutrophils did not produce phosphatidylinositol 3,4,5-trisphosphate, did not activate protein kinase B, and displayed impaired respiratory burst and motility. Peritoneal PI3Kgamma -null macrophages showed a reduced migration toward a wide range of chemotactic stimuli and a severely defective accumulation in a septic peritonitis model. These results demonstrate that PI3Kgamma is a crucial signaling molecule required for macrophage accumulation in inflammation.

1 Department of Genetics, Biology and Biochemistry, University of Torino, Turin, Italy.
2 Institute of Biochemistry, University of Fribourg, CH-1700 Fribourg, Switzerland.
3 Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
4 Section of General Pathology, University of Brescia, Brescia, Italy.
*   To whom correspondence should be addressed. E-mail: hirsch{at}molinette.unito.it and matthiaspaul.wymann{at}unifr.ch

dagger    These authors contributed equally to this work.

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Regulation of epidermal homeostasis and repair by phosphoinositide 3-kinase.
S. Pankow, C. Bamberger, A. Klippel, and S. Werner (2006)
J. Cell Sci. 119, 4033-4046
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DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration.
Z. Shulman, R. Pasvolsky, E. Woolf, V. Grabovsky, S. W. Feigelson, N. Erez, Y. Fukui, and R. Alon (2006)
Blood 108, 2150-2158
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Neutrophil Signaling Pathways Activated by Bacterial DNA Stimulation.
M. E. Alvarez, J. I. F. Bass, J. R. Geffner, P. X. F. Calotti, M. Costas, O. A. Coso, R. Gamberale, M. E. Vermeulen, G. Salamone, D. Martinez, et al. (2006)
J. Immunol. 177, 4037-4046
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To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front.
A. Van Keymeulen, K. Wong, Z. A. Knight, C. Govaerts, K. M. Hahn, K. M. Shokat, and H. R. Bourne (2006)
J. Cell Biol. 174, 437-445
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Class IA Phosphatidylinositide 3-Kinases, rather than p110{gamma}, Regulate Formyl-Methionyl-Leucyl-Phenylalanine-Stimulated Chemotaxis and Superoxide Production in Differentiated Neutrophil-Like PLB-985 Cells..
I. Boulven, S. Levasseur, S. Marois, G. Pare, E. Rollet-Labelle, and P. H. Naccache (2006)
J. Immunol. 176, 7621-7627
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Phosphatidylinositol 3-Kinase {gamma} Signaling through Protein Kinase C{zeta} Induces NADPH Oxidase-mediated Oxidant Generation and NF-{kappa}B Activation in Endothelial Cells.
R. S. Frey, X. Gao, K. Javaid, S. S. Siddiqui, A. Rahman, and A. B. Malik (2006)
J. Biol. Chem. 281, 16128-16138
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Evidence that phospholipase C-dependent, calcium-independent mechanisms are required for directional migration of T lymphocytes in response to the CCR4 ligands CCL17 and CCL22.
D. G. Cronshaw, A. Kouroumalis, R. Parry, A. Webb, Z. Brown, and S. G. Ward (2006)
J. Leukoc. Biol. 79, 1369-1380
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Costimulation of Chemokine Receptor Signaling by Matrix Metalloproteinase-9 Mediates Enhanced Migration of IFN-{alpha} Dendritic Cells.
Y. Hu and L. B. Ivashkiv (2006)
J. Immunol. 176, 6022-6033
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Toxoplasma gondii triggers Gi-dependent PI 3-kinase signaling required for inhibition of host cell apoptosis.
L. Kim and E. Y. Denkers (2006)
J. Cell Sci. 119, 2119-2126
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Membrane Electrical Activity Elicits Inositol 1,4,5-Trisphosphate-dependent Slow Ca2+ Signals through a Gbeta{gamma}/Phosphatidylinositol 3-Kinase {gamma} Pathway in Skeletal Myotubes.
J. M. Eltit, A. A. Garcia, J. Hidalgo, J. L. Liberona, M. Chiong, S. Lavandero, E. Maldonado, and E. Jaimovich (2006)
J. Biol. Chem. 281, 12143-12154
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Regulation of phosphatidylinositol 3-kinase by polyisoprenyl phosphates in neutrophil-mediated tissue injury.
C. Bonnans, K. Fukunaga, R. Keledjian, N. A. Petasis, and B. D. Levy (2006)
J. Exp. Med. 203, 857-863
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Characterization of p87PIKAP, a Novel Regulatory Subunit of Phosphoinositide 3-Kinase {gamma} That Is Highly Expressed in Heart and Interacts with PDE3B.
P. Voigt, M. B. Dorner, and M. Schaefer (2006)
J. Biol. Chem. 281, 9977-9986
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Opioids Trigger {alpha}5beta1 Integrin-Mediated Monocyte Adhesion.
O. M. Pello, B. Duthey, D. Garcia-Bernal, J. M. Rodriguez-Frade, J. V. Stein, J. Teixido, C. Martinez-A., and M. Mellado (2006)
J. Immunol. 176, 1675-1685
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Extracellular Acidosis Induces Neutrophil Activation by a Mechanism Dependent on Activation of Phosphatidylinositol 3-Kinase/Akt and ERK Pathways.
D. Martinez, M. Vermeulen, A. Trevani, A. Ceballos, J. Sabatte, R. Gamberale, M. E. Alvarez, G. Salamone, T. Tanos, O. A. Coso, et al. (2006)
J. Immunol. 176, 1163-1171
   Abstract »    Full Text »    PDF »
Knock-outs and inhibitors: one and the same?.
Z. A. Knight and K. M. Shokat (2006)
Blood 107, 420-421
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Key role of the p110{delta} isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110{delta} function in B cells.
A. Bilancio, K. Okkenhaug, M. Camps, J. L. Emery, T. Ruckle, C. Rommel, and B. Vanhaesebroeck (2006)
Blood 107, 642-650
   Abstract »    Full Text »    PDF »


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