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Science 287 (5455): 1040-1046

Copyright © 2000 by the American Association for the Advancement of Science

Function of PI3Kgamma in Thymocyte Development, T Cell Activation, and Neutrophil Migration

Takehiko Sasaki, 12 Junko Irie-Sasaki, 12 Russell G. Jones, 2 Antonio J. Oliveira-dos-Santos, 1 William L. Stanford, 3 Brad Bolon, 4 Andrew Wakeham, 1 Annick Itie, 1 Dennis Bouchard, 1 Ivona Kozieradzki, 1 Nicholas Joza, 1 Tak W. Mak, 12 Pamela S. Ohashi, 2 Akira Suzuki, 12 Josef M. Penninger 12*

Phosphoinositide 3-kinases (PI3Ks) regulate fundamental cellular responses such as proliferation, apoptosis, cell motility, and adhesion. Viable gene-targeted mice lacking the p110 catalytic subunit of PI3Kgamma were generated. We show that PI3Kgamma controls thymocyte survival and activation of mature T cells but has no role in the development or function of B cells. PI3Kgamma -deficient neutrophils exhibited severe defects in migration and respiratory burst in response to heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPCR) agonists and chemotactic agents. PI3Kgamma links GPCR stimulation to the formation of phosphatidylinositol 3,4,5-triphosphate and the activation of protein kinase B, ribosomal protein S6 kinase, and extracellular signal-regulated kinases 1 and 2. Thus, PI3Kgamma regulates thymocyte development, T cell activation, neutrophil migration, and the oxidative burst.

1 Amgen Institute, 620 University Avenue, Toronto M5G 2C1, Ontario, Canada.
2 Ontario Cancer Institute and the Departments of Medical Biophysics and Immunology;
3 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Department of Medical Genetics, University of Toronto, Toronto M5G 2C1, Ontario, Canada.
4 Department of Pathology, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320-1789, USA.
*   To whom correspondence should be addressed. E-mail: jpenning{at}

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Critical Roles of the p110{beta} Subtype of Phosphoinositide 3-Kinase in Lipopolysaccharide-Induced Akt Activation and Negative Regulation of Nitrite Production in RAW 264.7 Cells.
K. Tsukamoto, K. Hazeki, M. Hoshi, K. Nigorikawa, N. Inoue, T. Sasaki, and O. Hazeki (2008)
J. Immunol. 180, 2054-2061
   Abstract »    Full Text »    PDF »
Selective Regulation of CD8 Effector T Cell Migration by the p110{gamma} Isoform of Phosphatidylinositol 3-Kinase.
A. L. Martin, M. D. Schwartz, S. C. Jameson, and Y. Shimizu (2008)
J. Immunol. 180, 2081-2088
   Abstract »    Full Text »    PDF »
Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes.
S. J. Harris, R. V. Parry, J. Westwick, and S. G. Ward (2008)
J. Biol. Chem. 283, 2465-2469
   Abstract »    Full Text »    PDF »
The Molecular Basis of VEGFR-1 Signal Transduction Pathways in Primary Human Monocytes.
V. Tchaikovski, G. Fellbrich, and J. Waltenberger (2008)
Arterioscler Thromb Vasc Biol 28, 322-328
   Abstract »    Full Text »    PDF »
Small Molecule Disruption of G Protein {beta}{gamma} Subunit Signaling Inhibits Neutrophil Chemotaxis and Inflammation.
D. M. Lehmann, A. M. P. B. Seneviratne, and A. V. Smrcka (2008)
Mol. Pharmacol. 73, 410-418
   Abstract »    Full Text »    PDF »
CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer.
F. Garcon, D. T. Patton, J. L. Emery, E. Hirsch, R. Rottapel, T. Sasaki, and K. Okkenhaug (2008)
Blood 111, 1464-1471
   Abstract »    Full Text »    PDF »
Leptin Induces Macrophage Lipid Body Formation by a Phosphatidylinositol 3-Kinase- and Mammalian Target of Rapamycin-dependent Mechanism.
C. M. Maya-Monteiro, P. E. Almeida, H. D'Avila, A. S. Martins, A. P. Rezende, H. Castro-Faria-Neto, and P. T. Bozza (2008)
J. Biol. Chem. 283, 2203-2210
   Abstract »    Full Text »    PDF »
PI3K accelerates, but is not required for, neutrophil chemotaxis to fMLP.
B. Heit, L. Liu, P. Colarusso, K. D. Puri, and P. Kubes (2008)
J. Cell Sci. 121, 205-214
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinase {gamma} Gene Knockout Impairs Postischemic Neovascularization and Endothelial Progenitor Cell Functions.
P. Madeddu, N. Kraenkel, L. S. Barcelos, M. Siragusa, P. Campagnolo, A. Oikawa, A. Caporali, A. Herman, O. Azzolino, L. Barberis, et al. (2008)
Arterioscler Thromb Vasc Biol 28, 68-76
   Abstract »    Full Text »    PDF »
Protein kinase B (c-akt) regulates hematopoietic lineage choice decisions during myelopoiesis.
M. Buitenhuis, L. P. Verhagen, H. W. M. van Deutekom, A. Castor, S. Verploegen, L. Koenderman, S.-E. W. Jacobsen, and P. J. Coffer (2008)
Blood 111, 112-121
   Abstract »    Full Text »    PDF »
Altered Heart Rate and Sinoatrial Node Function in Mice Lacking the cAMP Regulator Phosphoinositide 3-Kinase-{gamma}.
R. A. Rose, M. G. Kabir, and P. H. Backx (2007)
Circ. Res. 101, 1274-1282
   Abstract »    Full Text »    PDF »
Tissue- and Stimulus-Dependent Role of Phosphatidylinositol 3-Kinase Isoforms for Neutrophil Recruitment Induced by Chemoattractants In Vivo.
V. Pinho, R. de Castro Russo, F. A. Amaral, L. P. de Sousa, M. M. Barsante, D. G. de Souza, J. C. Alves-Filho, D. C. Cara, J. S. Hayflick, C. Rommel, et al. (2007)
J. Immunol. 179, 7891-7898
   Abstract »    Full Text »    PDF »
Endothelial PI 3-kinase activity regulates lymphocyte diapedesis.
M. Nakhaei-Nejad, A. M. Hussain, Q.-X. Zhang, and A. G. Murray (2007)
Am J Physiol Heart Circ Physiol 293, H3608-H3616
   Abstract »    Full Text »    PDF »
Phosphoinositide 3 kinase {gamma} participates in T cell receptor induced T cell activation.
I. Alcazar, M. Marques, A. Kumar, E. Hirsch, M. Wymann, A. C. Carrera, and D. F. Barber (2007)
J. Exp. Med. 204, 2977-2987
   Abstract »    Full Text »    PDF »
Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes.
G. Shi, S. Partida-Sanchez, R. S. Misra, M. Tighe, M. T. Borchers, J. J. Lee, M. I. Simon, and F. E. Lund (2007)
J. Exp. Med. 204, 2705-2718
   Abstract »    Full Text »    PDF »

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