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Published Online July 18, 2002
Science DOI: 10.1126/science.1073560

Reports

Submitted on May 3, 2002
Accepted on July 3, 2002

Impaired B and T Cell Antigen Receptor Signaling in p110{delta} PI 3-Kinase Mutant Mice

Klaus Okkenhaug 1, Antonio Bilancio 1, Géraldine Farjot 1, Helen Priddle 2, Sara Sancho 3, Emma Peskett 1, Wayne Pearce 1, Stephen E. Meek 4, Ashreena Salpekar 1, Michael D. Waterfield 5, Andrew J. H. Smith 4, Bart Vanhaesebroeck 5*

1 Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK.
2 Roslin Institute, Roslin, Midlothian, EH25 9PS; Gene Targeting Laboratory, Center for Genome Research, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JQ, UK.
3 Frimorfo, Rue du Musée 12, CH-1705 Fribourg, Switzerland.
4 Gene Targeting Laboratory, Center for Genome Research, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JQ, UK.
5 Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK; Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.

* To whom correspondence should be addressed. E-mail: bartvanh{at}ludwig.ucl.ac.uk.

Class IA phosphoinositide 3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that generate second messenger signals downstream of tyrosine kinases, thereby controlling cell metabolism, growth, proliferation, differentiation, motility and survival. Mammals express three class IA catalytic subunits: p110{alpha}, p110ß, and p110{delta}. It is unclear to what extent these p110 isoforms have overlapping or distinct biological roles. To address this question, mice expressing a catalytically inactive form of p110{delta} (p110{delta}D910A) were generated by gene targeting. Antigen receptor signaling in B and T cells is impaired and immune responses in vivo are attenuated in p110{delta} mutant mice. In addition, they develop inflammatory bowel disease. These results reveal a selective role for p110{delta} in immunity.


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J. Biol. Chem. 279, 39775-39782
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Vav-Dependent and Vav-Independent Phosphatidylinositol 3-Kinase Activation in Murine B Cells Determined by the Nature of the Stimulus.
E. Vigorito, G. Bardi, J. Glassford, E. W.-F. Lam, E. Clayton, and M. Turner (2004)
J. Immunol. 173, 3209-3214
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Cutting Edge: Differential Roles for Phosphoinositide 3-Kinases, p110{gamma} and p110{delta}, in Lymphocyte Chemotaxis and Homing.
K. Reif, K. Okkenhaug, T. Sasaki, J. M. Penninger, B. Vanhaesebroeck, and J. G. Cyster (2004)
J. Immunol. 173, 2236-2240
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Enhanced T Cell Proliferation in Mice Lacking the p85{beta} Subunit of Phosphoinositide 3-Kinase.
J. A. Deane, M. J. Trifilo, C. M. Yballe, S. Choi, T. E. Lane, and D. A. Fruman (2004)
J. Immunol. 172, 6615-6625
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PI3-Kinase Upregulation and Involvement in Spontaneous Tone in Arteries From DOCA-Salt Rats: Is p110{delta} the Culprit?.
C. A. Northcott, J. S. Hayflick, and S. W. Watts (2004)
Hypertension 43, 885-890
   Abstract »    Full Text »    PDF »
Stable Gene Silencing in Human Monocytic Cell Lines Using Lentiviral-delivered Small Interference RNA: SILENCING OF THE p110{alpha} ISOFORM OF PHOSPHOINOSITIDE 3-KINASE REVEALS DIFFERENTIAL REGULATION OF ADHERENCE INDUCED BY 1{alpha},25-DIHYDROXYCHOLECALCIFEROL AND BACTERIAL LIPOPOLYSACCHARIDE.
J. S. Lee, Z. Hmama, A. Mui, and N. E. Reiner (2004)
J. Biol. Chem. 279, 9379-9388
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Phosphatidylinositol 3-Kinase-Dependent Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase 1/2 and NF-{kappa}B Signaling Pathways Are Required for B Cell Antigen Receptor-Mediated Cyclin D2 Induction in Mature B Cells.
M. J. Piatelli, C. Wardle, J. Blois, C. Doughty, B. R. Schram, T. L. Rothstein, and T. C. Chiles (2004)
J. Immunol. 172, 2753-2762
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Two Distinct Waves of Membrane-Proximal B Cell Antigen Receptor Signaling Differentially Regulated by Src Homology 2-Containing Inositol Polyphosphate 5-Phosphatase.
A. K. Krahn, K. Ma, S. Hou, V. Duronio, and A. J. Marshall (2004)
J. Immunol. 172, 331-339
   Abstract »    Full Text »    PDF »
Opportunities and challenges in the development of kinase inhibitor therapy for cancer.
C. L. Sawyers (2003)
Genes & Dev. 17, 2998-3010
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T-cell integrins: more than just sticking points.
N. Hogg, M. Laschinger, K. Giles, and A. McDowall (2003)
J. Cell Sci. 116, 4695-4705
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Class I Phosphoinositide 3-Kinase p110{beta} Is Required for Apoptotic Cell and Fc{gamma} Receptor-mediated Phagocytosis by Macrophages.
Y. Leverrier, K. Okkenhaug, C. Sawyer, A. Bilancio, B. Vanhaesebroeck, and A. J. Ridley (2003)
J. Biol. Chem. 278, 38437-38442
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The phosphoinositide (PI) 3-kinase family.
F. M. Foster, C. J. Traer, S. M. Abraham, and M. J. Fry (2003)
J. Cell Sci. 116, 3037-3040
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Phosphatidylinositol 3-Kinase Regulates the CD4/CD8 T Cell Differentiation Ratio.
L. Rodriguez-Borlado, D. F. Barber, C. Hernandez, M. A. Rodriguez-Marcos, A. Sanchez, E. Hirsch, M. Wymann, C. Martinez-A., and A. C. Carrera (2003)
J. Immunol. 170, 4475-4482
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Regulation of Breast Cancer Cell Chemotaxis by the Phosphoinositide 3-Kinase p110{delta}.
C. Sawyer, J. Sturge, D. C. Bennett, M. J. O'Hare, W. E. Allen, J. Bain, G. E. Jones, and B. Vanhaesebroeck (2003)
Cancer Res. 63, 1667-1675
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Critical Roles of Pten in B Cell Homeostasis and Immunoglobulin Class Switch Recombination.
A. Suzuki, T. Kaisho, M. Ohishi, M. Tsukio-Yamaguchi, T. Tsubata, P. A. Koni, T. Sasaki, T. W. Mak, and T. Nakano (2003)
J. Exp. Med. 197, 657-667
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Essential Role of Phosphoinositide 3-Kinase {delta} in Neutrophil Directional Movement.
C. Sadhu, B. Masinovsky, K. Dick, C. G. Sowell, and D. E. Staunton (2003)
J. Immunol. 170, 2647-2654
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B Cell Developmental Requirement for the G{alpha}i2 Gene.
H. Dalwadi, B. Wei, M. Schrage, T. T. Su, D. J. Rawlings, and J. Braun (2003)
J. Immunol. 170, 1707-1715
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Phosphoinositide 3-Kinase Activation by Igbeta Controls de Novo Formation of an Antigen-processing Compartment.
M. Granboulan, D. Lankar, G. Raposo, C. Bonnerot, and C. Hivroz (2003)
J. Biol. Chem. 278, 4331-4338
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Essential, Nonredundant Role for the Phosphoinositide 3-Kinase p110{delta} in Signaling by the B-Cell Receptor Complex.
S.-T. Jou, N. Carpino, Y. Takahashi, R. Piekorz, J.-R. Chao, N. Carpino, D. Wang, and J. N. Ihle (2002)
Mol. Cell. Biol. 22, 8580-8591
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Direct Effects of Caffeine and Theophylline on p110delta and Other Phosphoinositide 3-Kinases. DIFFERENTIAL EFFECTS ON LIPID KINASE AND PROTEIN KINASE ACTIVITIES.
L. C. Foukas, N. Daniele, C. Ktori, K. E. Anderson, J. Jensen, and P. R. Shepherd (2002)
J. Biol. Chem. 277, 37124-37130
   Abstract »    Full Text »    PDF »


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