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Science 11 February 2000:
Vol. 287. no. 5455, pp. 1040 - 1046
DOI: 10.1126/science.287.5455.1040
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Reports

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}amgen.com

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Essential role of PI3K{delta} and PI3K{gamma} in thymocyte survival.
W. Swat, V. Montgrain, T. A. Doggett, J. Douangpanya, K. Puri, W. Vermi, and T. G. Diacovo (2006)
Blood 107, 2415-2422
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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 »
Class IB-Phosphatidylinositol 3-Kinase (PI3K) Deficiency Ameliorates IA-PI3K-Induced Systemic Lupus but Not T Cell Invasion.
D. F. Barber, A. Bartolome, C. Hernandez, J. M. Flores, C. Fernandez-Arias, L. Rodriguez-Borlado, E. Hirsch, M. Wymann, D. Balomenos, and A. C. Carrera (2006)
J. Immunol. 176, 589-593
   Abstract »    Full Text »    PDF »
HIV-1 burden influences host response to co-infection with Neisseria gonorrhoeae in vitro.
M. Montano, M. Rarick, P. Sebastiani, P. Brinkmann, J. Skefos, and R. Ericksen (2006)
Int. Immunol. 18, 125-137
   Abstract »    Full Text »    PDF »
Targeted Deletion of Integrin-Linked Kinase Reveals a Role in T-Cell Chemotaxis and Survival.
E. Liu, S. Sinha, C. Williams, M. Cyrille, E. Heller, S. B. Snapper, K. Georgopoulos, R. St-Arnaud, T. Force, S. Dedhar, et al. (2005)
Mol. Cell. Biol. 25, 11145-11155
   Abstract »    Full Text »    PDF »
Role of phosphatidylinositol 3-kinase-{gamma} in mediating lung neutrophil sequestration and vascular injury induced by E. coli sepsis.
E. Ong, X.-P. Gao, D. Predescu, M. Broman, and A. B. Malik (2005)
Am J Physiol Lung Cell Mol Physiol 289, L1094-L1103
   Abstract »    Full Text »    PDF »
Plasma Membrane Organization Is Essential for Balancing Competing Pseudopod- and Uropod-promoting Signals during Neutrophil Polarization and Migration.
S. Bodin and M. D. Welch (2005)
Mol. Biol. Cell 16, 5773-5783
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Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute {beta}-adrenergic stimulation.
Y.-T. Tseng, N. Yano, A. Rojan, J. P. Stabila, B. G. McGonnigal, V. Ianus, R. Wadhawan, and J. F. Padbury (2005)
Am J Physiol Heart Circ Physiol 289, H1834-H1842
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Mammalian G Proteins and Their Cell Type Specific Functions.
N. Wettschureck and S. Offermanns (2005)
Physiol Rev 85, 1159-1204
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"Host Tissue Damage" Signal ATP Promotes Non-directional Migration and Negatively Regulates Toll-like Receptor Signaling in Human Monocytes.
A. Kaufmann, B. Musset, S. H. Limberg, V. Renigunta, R. Sus, A. H. Dalpke, K. M. Heeg, B. Robaye, and P. J. Hanley (2005)
J. Biol. Chem. 280, 32459-32467
   Abstract »    Full Text »    PDF »
New approaches to COPD.
P. J. Barnes (2005)
Eur. Respir. Rev. 14, 2-11
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Cutting Edge: T Cell Development Requires the Combined Activities of the p110{gamma} and p110{delta} Catalytic Isoforms of Phosphatidylinositol 3-Kinase.
L. M. C. Webb, E. Vigorito, M. P. Wymann, E. Hirsch, and M. Turner (2005)
J. Immunol. 175, 2783-2787
   Abstract »    Full Text »    PDF »
The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis.
K. Hamada, T. Sasaki, P. A. Koni, M. Natsui, H. Kishimoto, J. Sasaki, N. Yajima, Y. Horie, G. Hasegawa, M. Naito, et al. (2005)
Genes & Dev. 19, 2054-2065
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Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils.
A. M. Condliffe, K. Davidson, K. E. Anderson, C. D. Ellson, T. Crabbe, K. Okkenhaug, B. Vanhaesebroeck, M. Turner, L. Webb, M. P. Wymann, et al. (2005)
Blood 106, 1432-1440
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Ligand-Induced Partitioning of Human CXCR1 Chemokine Receptors with Lipid Raft Microenvironments Facilitates G-Protein-Dependent Signaling.
X. Jiao, N. Zhang, X. Xu, J. J. Oppenheim, and T. Jin (2005)
Mol. Cell. Biol. 25, 5752-5762
   Abstract »    Full Text »    PDF »
LPA2 receptor mediates mitogenic signals in human colon cancer cells.
C. C. Yun, H. Sun, D. Wang, R. Rusovici, A. Castleberry, R. A. Hall, and H. Shim (2005)
Am J Physiol Cell Physiol 289, C2-C11
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The role of endothelial PI3K{gamma} activity in neutrophil trafficking.
K. D. Puri, T. A. Doggett, C.-Y. Huang, J. Douangpanya, J. S. Hayflick, M. Turner, J. Penninger, and T. G. Diacovo (2005)
Blood 106, 150-157
   Abstract »    Full Text »    PDF »
COPD: current therapeutic interventions and future approaches.
P. J. Barnes and R. A. Stockley (2005)
Eur. Respir. J. 25, 1084-1106
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Cardiac Sarcoplasmic Reticulum Calcium Release and Load Are Enhanced by Subcellular cAMP Elevations in PI3K{gamma}-Deficient Mice.
B.-G. Kerfant, D. Gidrewicz, H. Sun, G. Y. Oudit, J. M. Penninger, and P. H. Backx (2005)
Circ. Res. 96, 1079-1086
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Phosphoinositide-3 kinases critically regulate the recruitment and survival of eosinophils in vivo: importance for the resolution of allergic inflammation.
V. Pinho, D. G. Souza, M. M. Barsante, F. P. Hamer, M. S. De Freitas, A. G. Rossi, and M. M. Teixeira (2005)
J. Leukoc. Biol. 77, 800-810
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The Unique N-Terminus of R-Ras Is Required for Rac Activation and Precise Regulation of Cell Migration.
S. P. Holly, M. K. Larson, and L. V. Parise (2005)
Mol. Biol. Cell 16, 2458-2469
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Protein O-GlcNAc Modulates Motility-associated Signaling Intermediates in Neutrophils.
Z. T. Kneass and R. B. Marchase (2005)
J. Biol. Chem. 280, 14579-14585
   Abstract »    Full Text »    PDF »
Future Directions in the Pharmacologic Therapy of Chronic Obstructive Pulmonary Disease.
R. Buhl and S. G. Farmer (2005)
Proceedings of the ATS 2, 83-93
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