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Sci. Signal., 10 August 2010
Vol. 3, Issue 134, p. ra60
[DOI: 10.1126/scisignal.2001104]

RESEARCH ARTICLES

The PI3K Isoforms p110{alpha} and p110{delta} Are Essential for Pre–B Cell Receptor Signaling and B Cell Development

Faruk Ramadani1, Daniel J. Bolland2, Fabien Garcon1, Juliet L. Emery1, Bart Vanhaesebroeck3, Anne E. Corcoran2, and Klaus Okkenhaug1*

1 Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, UK.
2 Chromatin and Gene Expression, Babraham Institute, Cambridge CB22 3AT, UK.
3 Centre for Cell Signaling, Institute of Cancer, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

Abstract: B cell development is controlled by a series of checkpoints that ensure that the immunoglobulin (Ig)–encoding genes produce a functional B cell receptor (BCR) and antibodies. As part of this process, recombination-activating gene (Rag) proteins regulate the in-frame assembly of the Ig-encoding genes. The BCR consists of Ig proteins in complex with the immunoreceptor tyrosine-based activation motif (ITAM)–containing Ig{alpha} and Igβ chains. Whereas the activation of the tyrosine kinases Src and Syk is essential for BCR signaling, the pathways that act downstream of these kinases are incompletely defined. Previous work has revealed a key role for the p110{delta} isoform of phosphatidylinositol 3-kinase (PI3K) in agonist-induced BCR signaling; however, early B cell development and mature B cell survival, which depend on agonist-independent or "tonic" BCR signaling, are not substantially affected by a deficiency in p110{delta}. Here, we show that p110{alpha}, but not p110β, compensated in the absence of p110{delta} to promote early B cell development in the bone marrow and B cell survival in the spleen. In the absence of both p110{alpha} and p110{delta} activities, pre-BCR signaling failed to suppress the production of Rag proteins and to promote developmental progression of B cell progenitors. Unlike p110{delta}, however, p110{alpha} did not contribute to agonist-induced BCR signaling. These studies indicate that either p110{alpha} or p110{delta} can mediate tonic signaling from the BCR, but only p110{delta} can contribute to antigen-dependent activation of B cells.

* To whom correspondence should be addressed. E-mail: klaus.okkenhaug{at}bbsrc.ac.uk

Citation: F. Ramadani, D. J. Bolland, F. Garcon, J. L. Emery, B. Vanhaesebroeck, A. E. Corcoran, K. Okkenhaug, The PI3K Isoforms p110{alpha} and p110{delta} Are Essential for Pre–B Cell Receptor Signaling and B Cell Development. Sci. Signal. 3, ra60 (2010).

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