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Impaired B and T Cell Antigen Receptor Signaling in p110 PI 3-Kinase Mutant Mice
Klaus Okkenhaug,1Antonio Bilancio,1*Géraldine Farjot,1*Helen Priddle,2*Sara Sancho,3Emma Peskett,1Wayne Pearce,1Stephen E. Meek,2Ashreena Salpekar,1Michael D. Waterfield,14Andrew J. H. Smith,2Bart Vanhaesebroeck14
Class IA phosphoinositide 3-kinases (PI3Ks) are a
family of p85/p110 heterodimeric lipid kinases that generate second
messengersignals downstream of tyrosine kinases, thereby controlling
cellmetabolism, growth, proliferation, differentiation, motility,and
survival. Mammals express three class IA catalytic subunits:p110,
p110, and p110. It is unclear to what extent these p110isoforms
have overlapping or distinct biological roles. Mice expressinga
catalytically inactive form of p110
(p110D910A) were generated by gene targeting.
Antigen receptor signalingin B and T cells was impaired and immune
responses in vivo wereattenuated in p110 mutant mice. They also
developed inflammatorybowel disease. These results reveal a selective
role for p110in immunity.
1 Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK.
2 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 Department of Biochemistry and
Molecular Biology, University College London, Gower Street, London WC1E
6BT, UK.
*
These authors contributed equally to this report.
Present address: Roslin Institute, Roslin, Midlothian,
EH25 9PS, UK.
To whom correspondence should be addressed. E-mail:
bartvanh{at}ludwig.ucl.ac.uk
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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 »
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 »
The Effect of Deleting p110{delta} on the Phenotype and Function of PTEN-Deficient B Cells.
M. L. Janas, D. Hodson, Z. Stamataki, S. Hill, K. Welch, L. Gambardella, L. C. Trotman, P. P. Pandolfi, E. Vigorito, and M. Turner (2008)
J. Immunol.
180, 739-746
|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 »
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 »
The p110delta catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion.
N. Kim, A. Saudemont, L. Webb, M. Camps, T. Ruckle, E. Hirsch, M. Turner, and F. Colucci (2007)
Blood
110, 3202-3208
|Abstract »|Full Text »|PDF »
Inactivation of PI3K{gamma} and PI3K{delta} distorts T-cell development and causes multiple organ inflammation.
H. Ji, F. Rintelen, C. Waltzinger, D. Bertschy Meier, A. Bilancio, W. Pearce, E. Hirsch, M. P. Wymann, T. Ruckle, M. Camps, et al. (2007)
Blood
110, 2940-2947
|Abstract »|Full Text »|PDF »
Quantitative Profile of Five Murine Core Proteomes Using Label-free Functional Proteomics.
P. R. Cutillas and B. Vanhaesebroeck (2007)
Mol. Cell. Proteomics
6, 1560-1573
|Abstract »|Full Text »|PDF »
The Recirculating B Cell Pool Contains Two Functionally Distinct, Long-Lived, Posttransitional, Follicular B Cell Populations.
A. Cariappa, C. Boboila, S. T. Moran, H. Liu, H. N. Shi, and S. Pillai (2007)
J. Immunol.
179, 2270-2281
|Abstract »|Full Text »|PDF »
Synergism between NF-{kappa}B1/p50 and Notch2 during the Development of Marginal Zone B Lymphocytes.
S. T. Moran, A. Cariappa, H. Liu, B. Muir, D. Sgroi, C. Boboila, and S. Pillai (2007)
J. Immunol.
179, 195-200
|Abstract »|Full Text »|PDF »
Abnormal hematopoiesis in Gab2 mutant mice.
Y. Zhang, E. Diaz-Flores, G. Li, Z. Wang, Z. Kang, E. Haviernikova, S. Rowe, C.-K. Qu, W. Tse, K. M. Shannon, et al. (2007)
Blood
110, 116-124
|Abstract »|Full Text »|PDF »
Phosphoinositide 3-kinase signalling regulates early development and developmental haemopoiesis.
PI 3-Kinase Mutant Mice
,
p110
, and p110
. It is unclear to what extent these p110 isoforms
have overlapping or distinct biological roles. Mice expressing a
catalytically inactive form of p110
